Submissions for variant NM_004415.4(DSP):c.2773C>T (p.Arg925Trp)

gnomAD frequency: 0.00143  dbSNP: rs145933612

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038015	SCV000061681	likely benign	not specified	2015-11-09	criteria provided, single submitter	clinical testing	p.Arg925Trp in exon 19 of DSP: This variant is not expected to have clinical sig nificance because it has been identified in 0.4% (45/10296) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs145933612).
GeneDx	RCV001719746	SCV000233599	likely benign	not provided	2021-06-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25351510)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238651	SCV000297155	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-09-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000370699	SCV000464954	likely benign	Woolly hair-skin fragility syndrome	2018-02-22	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	RCV000276162	SCV000464955	likely benign	Lethal acantholytic epidermolysis bullosa	2018-02-22	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	RCV001095285	SCV000464956	likely benign	Arrhythmogenic right ventricular dysplasia 8	2018-02-22	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	RCV000473091	SCV000555781	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771365	SCV000903660	likely benign	Cardiomyopathy	2018-06-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038015	SCV000917293	likely benign	not specified	2017-11-21	criteria provided, single submitter	clinical testing	Variant summary: The DSP c.2773C>T (p.Arg925Trp) variant involves the alteration of a conserved nucleotide that is located in the Spectrin/alpha-actinin domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 140/277128 control chromosomes, including 1 homozygote, at a frequency of 0.0005052, which is approximately 51 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001), suggesting this variant is likely a benign polymorphism. Additionally, the variant was found in 105/24026 African control chromosomes, a frequency of 0.00437, which is approximately 437 times above the maximal expected allele frequency, suggesting it is most prevalent in this subpopulation and further supporting a benign impact of the variant. The variant has been cited in the literature without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256834	SCV001433319	likely benign	Dilated cardiomyopathy 1A	2019-12-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001719746	SCV001473127	uncertain significance	not provided	2020-08-23	criteria provided, single submitter	clinical testing	The DSP c.2773C>T, p.Arg925Trp variant (rs145933612), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 44881). This variant is found in the African population with an allele frequency of 0.2% (108/24,952 alleles) in the Genome Aggregation Database. The arginine at codon 925 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Arg925Trp variant is uncertain at this time. Gene statement: Pathogenic variants in DSP are associated with autosomal dominant arrhythmogenic right ventricular dysplasia 8 (MIM: 607450), dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (MIM: 615821), and keratosis palmoplantaris striata II (MIM: 612908), and autosomal recessive dilated cardiomyopathy with woolly hair and keratoderma (MIM: 605676), lethal acantholytic epidermolysis bullosa (MIM: 609638), and skin fragility-woolly hair syndrome (MIM: 607655).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771365	SCV002043288	benign	Cardiomyopathy	2019-10-28	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224123	SCV003919899	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.Arg925Trp (c.2773C>T): This variant has not been reported in the literature and is present in 0.4% (108/24952) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/6-7576669-C-T). This variant is also present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:44881). However, 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.
CeGaT Center for Human Genetics Tuebingen	RCV001719746	SCV004011651	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	DSP: BP4
Ambry Genetics	RCV004017316	SCV004849006	likely benign	Cardiovascular phenotype	2019-05-01	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.
PreventionGenetics, part of Exact Sciences	RCV003964855	SCV004784265	likely benign	DSP-related disorder	2019-04-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).