Submissions for variant NM_004415.4(DSP):c.1696G>A (p.Ala566Thr)

gnomAD frequency: 0.00026  dbSNP: rs148147581

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150560	SCV000197800	likely benign	not specified	2017-12-05	criteria provided, single submitter	clinical testing	p.Ala566Thr in exon 13 of DSP: This variant is not expected to have clinical sig nificance because it has been identified in 0.03% (40/126324) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP ${MatchVariant_1_dbSNPrsNumber}). ACMG/AMP Criteria applied: BS1.
GeneDx	RCV000766877	SCV000233584	uncertain significance	not provided	2024-01-19	criteria provided, single submitter	clinical testing	Published in association with ARVC, HCM, and DCM, and found to independently segregate with disease in a relative of a proband with ARVC (PMID: 16774985, 21606396, 27000522, 25351510, 28045975); Functional studies suggest that the p.(A566T) variant alone is insufficient to impair protein function (PMID: 25225338); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24055113, 21606396, 23299917, 26332594, 25351510, 28045975, 31402444, 26606670, 31785789, 36142674, 22949226, 33652588, 35653365, 16774985, 27000522, 25225338)
Illumina Laboratory Services, Illumina	RCV000284191	SCV000464898	likely benign	Lethal acantholytic epidermolysis bullosa	2019-01-31	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000735747	SCV000464899	likely benign	Arrhythmogenic right ventricular dysplasia 8	2019-01-31	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000285554	SCV000464901	likely benign	Woolly hair-skin fragility syndrome	2019-01-31	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476727	SCV000543275	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2025-01-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515316	SCV000611474	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	2017-05-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617402	SCV000738242	likely benign	Cardiovascular phenotype	2022-02-28	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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626864	SCV000747567	uncertain significance	Palmoplantar blistering; Skin fragility with non-scarring blistering	2017-01-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771793	SCV000904482	likely benign	Cardiomyopathy	2019-11-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000766877	SCV003829141	uncertain significance	not provided	2021-04-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000766877	SCV004227187	uncertain significance	not provided	2022-04-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150560	SCV005204851	likely benign	not specified	2024-06-10	criteria provided, single submitter	clinical testing	Variant summary: DSP c.1696G>A (p.Ala566Thr) results in a non-conservative amino acid change located in the spectrin-like domain (IPR041573) of 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 0.0002 in 251036 control chromosomes, predominantly at a frequency of 0.00034 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002). The variant, c.1696G>A, has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and other cardiac phenotypes, however several of these reported affected individuals carried a co-occurring (likely) pathogenic variant, which could explain the phenotype (e.g. Cox_2011, Begay_2016, Franaszczyk_2017). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated no significant changes for the A566T variant (Patel_2014). The following publications have been ascertained in the context of this evaluation (PMID: 21606396, 28008423, 28045975, 25225338). ClinVar contains an entry for this variant (Variation ID: 161226). Based on the evidence outlined above, the variant was classified as likely benign.
CSER _CC_NCGL, University of Washington	RCV000148476	SCV000190178	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2014-06-01	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000735747	SCV000863904	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2018-06-18	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000150560	SCV001919452	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766877	SCV001929270	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766877	SCV001965457	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766877	SCV001979531	likely benign	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483521	SCV004228795	not provided	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.