Submissions for variant NM_004415.4(DSP):c.1949A>G (p.Asn650Ser)

gnomAD frequency: 0.00016  dbSNP: rs145650440

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038003	SCV000061669	uncertain significance	not specified	2013-10-14	criteria provided, single submitter	clinical testing	The Asn650Ser variant in DSP has now been identified by our laboratory in 2 Blac k individuals with HCM, 1 of whom carried a pathogenic variant in another gene. This variant has also been identified in 1/4406 African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1 45650440). Computational analyses (biochemical amino acid properties, conservati on, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical significance of this variant.
Invitae	RCV000469452	SCV000543271	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001175862	SCV001339641	likely benign	Cardiomyopathy	2019-12-02	criteria provided, single submitter	clinical testing
Genetics and Genomics Program, Sidra Medicine	RCV001293188	SCV001434186	likely benign	Primary dilated cardiomyopathy		criteria provided, single submitter	research
GeneDx	RCV001564615	SCV001787807	uncertain significance	not provided	2020-11-27	criteria provided, single submitter	clinical testing	Reported in a patient with cardiomyopathy (van Lint et al., 2019); however, detailed clinical information was not provided; Reported in ClinVar (ClinVar Variant ID# 44869; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038003	SCV002572083	uncertain significance	not specified	2022-08-16	criteria provided, single submitter	clinical testing	Variant summary: DSP c.1949A>G (p.Asn650Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 282332 control chromosomes (gnomAD), predominantly at a frequency of 0.0004 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (0.0002), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1949A>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy (van Lint_2019, Al-Shafai_2021), but these reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV004018856	SCV004859847	benign	Cardiovascular phenotype	2024-06-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.