VCV000030875.3 - ClinVar

NM_020223.4(FAM20C):c.1351G>A (p.Asp451Asn)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020223.4(FAM20C):c.1351G>A (p.Asp451Asn)

Variation ID: 30875 Accession: VCV000030875.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p22.3 7: 256751 (GRCh38) [ NCBI UCSC ] 7: 296717 (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	Aug 5, 2015	Dec 24, 2022	Jun 15, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_020223.4:c.1351G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_064608.2:p.Asp451Asn	missense
NC_000007.14:g.256751G>A
NC_000007.13:g.296717G>A
NG_033970.1:g.66387G>A

Protein change

D451N

Other names

D437N

Canonical SPDI

NC_000007.14:256750:G:A

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

OMIM: 611061.0009 dbSNP: rs2115173146 ClinGen: CA366525682 VarSome

Comment on variant

NCBI staff reviewed the context of the sequence variant reported in the paper by Simpson et al., 2009, Fig. 3 (PubMed 19250384) to establish the location of this variant.

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.
FAM20C		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	488	543

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.
Lethal osteosclerotic bone dysplasia	Pathogenic (1)	no assertion criteria provided	Mar 1, 2009	RCV000023860.5
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jun 15, 2022	RCV002468976.1

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.
Likely pathogenic (Jun 15, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002765883.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: Observed with another FAM20C variant in a patient with features of Raine syndrome in published literature, but it is not known whether the variants occurred … (more) Observed with another FAM20C variant in a patient with features of Raine syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Kumar Girigiri et al., 2021); Published functional studies demonstrate a damaging effect: impaired secretion, impaired phosphorylation of OPN and DMP1, and increased endoplasmic reticulum stress response (Kinoshita et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.1309G>A p.D437N; This variant is associated with the following publications: (PMID: Girigiri2021[caseReport], 32299476, 19250384, 32833257, 34360805, 25026495) (less)
Pathogenic (Mar 01, 2009)	no assertion criteria provided Method: literature only	RAINE SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000045151.3 First in ClinVar: Apr 04, 2013 Last updated: Aug 05, 2015	Publications: PubMed (1) PubMed: 19250384 Comment on evidence: In an 8-year-old boy with Raine syndrome (RNS; 259775), Simpson et al. (2009) identified homozygosity for a 1309G-A transition in exon 7 of the FAM20C … (more) In an 8-year-old boy with Raine syndrome (RNS; 259775), Simpson et al. (2009) identified homozygosity for a 1309G-A transition in exon 7 of the FAM20C gene, resulting in an asp437-to-asn (D437N) substitution at a highly conserved residue within the conserved C-terminal domain (CCD). The mutation, which was present in heterozygosity in his unaffected parents, was not found in more than 300 control chromosomes. (less)

Comment:

Observed with another FAM20C variant in a patient with features of Raine syndrome in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Kumar Girigiri et al., 2021); Published functional studies demonstrate a damaging effect: impaired secretion, impaired phosphorylation of OPN and DMP1, and increased endoplasmic reticulum stress response (Kinoshita et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.1309G>A p.D437N; This variant is associated with the following publications: (PMID: Girigiri2021[caseReport], 32299476, 19250384, 32833257, 34360805, 25026495)

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
Mutations in FAM20C also identified in non-lethal osteosclerotic bone dysplasia.	Simpson MA	Clinical genetics	2009	PMID: 19250384

Text-mined citations for rs2115173146 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 25, 2023

ClinVar Genomic variation as it relates to human health

NM_020223.4(FAM20C):c.1351G>A (p.Asp451Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2115173146 ...