VCV002821928.1 - ClinVar

NM_002778.4(PSAP):c.158G>A (p.Trp53Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002778.4(PSAP):c.158G>A (p.Trp53Ter)

Variation ID: 2821928 Accession: VCV002821928.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q22.1 10: 71834388 (GRCh38) [ NCBI UCSC ] 10: 73594145 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 20, 2024	Dec 7, 2024	Nov 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002778.4:c.158G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002769.1:p.Trp53Ter	nonsense
NM_001042465.3:c.158G>A	NP_001035930.1:p.Trp53Ter	nonsense
NM_001042466.3:c.158G>A	NP_001035931.1:p.Trp53Ter	nonsense
NC_000010.11:g.71834388C>T
NC_000010.10:g.73594145C>T
NG_009301.1:g.21938G>A

... more HGVS ... less HGVS

Protein change

W53*

Other names

NM_002778.4(PSAP):c.158G>A
p.Trp53Ter

Canonical SPDI

NC_000010.11:71834387:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA377155775 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PSAP		-	-	GRCh38 GRCh37	879	936

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Sphingolipid activator protein 1 deficiency	Pathogenic (1)	criteria provided, single submitter	May 5, 2023	RCV003628021.2
Neuromuscular disease	Uncertain significance (1)	criteria provided, single submitter	Nov 27, 2024	RCV004797646.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Sphingolipid activator protein 1 deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004486404.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 8554069‚ 11309366‚ 17616409‚ 19267410‚ 30632081 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PSAP-related conditions. … (more) For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PSAP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp53*) in the PSAP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PSAP are known to be pathogenic (PMID: 8554069, 11309366, 17616409, 19267410, 30632081). (less)
Uncertain Significance (Nov 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Neuromuscular disease (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Study: GREGoR Consortium Accession: SCV005419126.1 First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024	Comment: The heterozygous p.Trp53Ter variant in PSAP was identified by our study, in the compound heterozygous state with another variant of uncertain significance, in 1 individual … (more) The heterozygous p.Trp53Ter variant in PSAP was identified by our study, in the compound heterozygous state with another variant of uncertain significance, in 1 individual with a predominantly motor axonal neuropathy/neuronopathy. While this gene is still lacking sufficient evidence, we believe this is a possible phenotypic expansion. Given the limited information about this gene-disease relationship, the significance of the p.Trp53Ter variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in PSAP we encourage you to reach out to us. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with PSAP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp53*) in the PSAP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PSAP are known to be pathogenic (PMID: 8554069, 11309366, 17616409, 19267410, 30632081).

Comment:

The heterozygous p.Trp53Ter variant in PSAP was identified by our study, in the compound heterozygous state with another variant of uncertain significance, in 1 individual with a predominantly motor axonal neuropathy/neuronopathy. While this gene is still lacking sufficient evidence, we believe this is a possible phenotypic expansion. Given the limited information about this gene-disease relationship, the significance of the p.Trp53Ter variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in PSAP we encourage you to reach out to us.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Late Infantile Metachromatic Leukodystrophy Due to Novel Pathogenic Variants in the PSAP Gene.	Kolnikova M	Journal of molecular neuroscience : MN	2019	PMID: 30632081
Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations.	Kuchar L	American journal of medical genetics. Part A	2009	PMID: 19267410
Metachromatic leukodystrophy without arylsulfatase A deficiency: a new case of saposin-B deficiency.	Deconinck N	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2008	PMID: 17616409
A novel mutation in the coding region of the prosaposin gene leads to a complete deficiency of prosaposin and saposins, and is associated with a complex sphingolipidosis dominated by lactosylceramide accumulation.	Hulková H	Human molecular genetics	2001	PMID: 11309366
Analysis of a splice-site mutation in the sap-precursor gene of a patient with metachromatic leukodystrophy.	Henseler M	American journal of human genetics	1996	PMID: 8554069

Text-mined citations for this variant ...

Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_002778.4(PSAP):c.158G>A (p.Trp53Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...