Submissions for variant NM_004415.4(DSP):c.8496ATCTCGCTCCGG[1] (p.2827SGSR[4])

dbSNP: rs397516971

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038112	SCV000061778	likely benign	not specified	2015-02-18	criteria provided, single submitter	clinical testing	p.Ser2843_Arg2846del in exon 24 of DSP: This variant is not expected to have cli nical significance because it has been identified in 0.4% (50/11494) of Latino c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org). This in-frame deletion of four amino acids occurs within a region of repe ating amino acids. It can result from several different DNA deletions, and is pr esent in mammals (dolphin, opossum, and platypus) and other evolutionarily dista nt species.
GeneDx	RCV000845325	SCV000233697	likely benign	not provided	2018-07-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27532257, 24503780, 21636032, 25445213, 31402444)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079689	SCV000641358	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-31	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845325	SCV000987371	uncertain significance	not provided		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001186904	SCV001353514	likely benign	Cardiomyopathy	2018-11-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038112	SCV001360929	benign	not specified	2019-07-08	criteria provided, single submitter	clinical testing	Variant summary: DSP c.8508_8519del12 (p.Ser2843_Arg2846del) results in an in-frame deletion that is predicted to remove four amino acids from a repetitive region at the C-terminus of the protein (of note, this protein level change can be a result of several different DNA deletions). The variant allele was found at a frequency of 0.0003 in 278122 control chromosomes, predominantly at a frequency of 0.0015 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 7.5 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. Though the variant has been reported in the literature in one individual affected with Arrhythmogenic Right Ventricular Cardiomyopathy (Green_2014), it was also described in a healthy control (Kapplinger_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001186904	SCV002043309	likely benign	Cardiomyopathy	2021-03-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408516	SCV002675433	likely benign	Cardiovascular phenotype	2018-09-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.