Submissions for variant NM_024422.6(DSC2):c.408A>G (p.Arg136=)

gnomAD frequency: 0.00004  dbSNP: rs561653481

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000250186	SCV000319151	benign	Cardiovascular phenotype	2021-08-04	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Invitae	RCV000533412	SCV000645017	likely benign	Arrhythmogenic right ventricular dysplasia 11	2023-09-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771973	SCV000904927	likely benign	Cardiomyopathy	2023-12-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000533412	SCV001282913	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2019-09-09	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223837	SCV001623188	uncertain significance	not specified	2021-04-20	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.408A>G alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic exonic 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.4e-05 in 251304 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (4.4e-05 vs 0.00016), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.408A>G in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=3, likely benign, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223837	SCV000280079	uncertain significance	not specified	2014-05-16	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. This variant is located in exon 4 (of 16 exons) does not change the amino acid at codon 136, however BDGP and ESEfinder splice prediction tools predict this alteration to create an alternate donor splice site. There is no direct function evidence available. The arginine at codon 136 is conserved across species, as are neighboring amino acids. In total the variant has not been seen in ~6,500 individuals from publicly available population datasets. There is no variation at codon 136 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 11/22/13). Note that this dataset does not match the patient's ancestry (Asian). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 11/22/13).