Submissions for variant NM_004415.4(DSP):c.2683T>C (p.Tyr895His)

gnomAD frequency: 0.00043  dbSNP: rs375891215

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766878	SCV000321565	likely benign	not provided	2020-03-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28611029)
Invitae	RCV001085987	SCV000543256	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000255188	SCV000710900	uncertain significance	not specified	2017-12-15	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Tyr895His var iant in DSP has been reported in 1 individual with DCM (Haskell 2017). It has be en identified in 0.14% (34/24034) of African chromosomes by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs375891215). This variant has also been reported in ClinVar (Variation ID:265103). Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, while the clinical significance of the p.Tyr895His variant is uncertain, its frequency suggests that it is more lik ely to be benign. ACMG/AMP Criteria applied: BS1.
Color Diagnostics, LLC DBA Color Health	RCV001184769	SCV001350831	likely benign	Cardiomyopathy	2019-11-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000255188	SCV002511688	likely benign	not specified	2022-04-05	criteria provided, single submitter	clinical testing	Variant summary: DSP c.2683T>C (p.Tyr895His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251300 control chromosomes, predominantly at a frequency of 0.0014 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 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2683T>C has been reported in the literature in an individual affected with DCM, without strong evidence for causality (Haskell_2017). This report does 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified the variant as likely benign while three classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002450789	SCV002739084	likely benign	Cardiovascular phenotype	2021-01-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224246	SCV003919897	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2021-03-30	criteria provided, single submitter	clinical testing	DSP NM_004415.3 exon 19 p.Tyr895His (c.2683T>C): This variant has been reported in the literature in one individual with DCM (Haskell 2017 PMID:28611029). This variant is also present in 0.1% (33/24972) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/6-7576579-T-C) and is present in ClinVar (Variation ID:265103). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678703	SCV000804867	uncertain significance	Left ventricular hypertrophy	2015-11-04	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678704	SCV000804868	uncertain significance	Sudden death	2017-06-16	no assertion criteria provided	clinical testing