Submissions for variant NM_004415.4(DSP):c.2773C>T (p.Arg925Trp) (rs145933612)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare 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	RCV000038015	SCV000233599	likely benign	not specified	2017-11-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia	RCV000238651	SCV000297155	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-09-24	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000370699	SCV000464954	likely benign	Skin fragility-woolly hair-palmoplantar keratoderma 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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina	RCV001095285	SCV000464956	likely benign	Arrhythmogenic right ventricular cardiomyopathy, type 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.
Illumina Clinical Services Laboratory,Illumina	RCV000381091	SCV000464957	likely benign	Epidermolysis bullosa simplex due to plakophilin deficiency	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000473091	SCV000555781	likely benign	Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8	2019-12-31	criteria provided, single submitter	clinical testing
Color	RCV000771365	SCV000903660	likely benign	Cardiomyopathy	2018-06-05	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	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.