Submissions for variant NM_004415.4(DSP):c.8455A>C (p.Met2819Leu)

gnomAD frequency: 0.00103  dbSNP: rs138329459

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172546	SCV000050926	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038105	SCV000061771	benign	not specified	2017-09-11	criteria provided, single submitter	clinical testing	p.Met2819Leu in Exon 24 of DSP: This variant is not expected to have clinical si gnificance because it has been identified in 1.25% (428/34228) Latino chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs138329459).
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203133	SCV000257971	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-05-05	criteria provided, single submitter	clinical testing
Invitae	RCV001085488	SCV000288550	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095186	SCV000465254	likely benign	Arrhythmogenic right ventricular dysplasia 8	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000392037	SCV000465255	benign	Woolly hair-skin fragility syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000337923	SCV000465257	benign	Lethal acantholytic epidermolysis bullosa	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000172546	SCV000698451	benign	not provided	2017-03-06	criteria provided, single submitter	clinical testing	Variant summary: The DSP c.8455A>C (p.Met2819Leu) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant . This variant was found in 212/122592 control chromosomes (2 homozygotes), predominantly observed in the Latino subpopulation at a frequency of 0.014686 (170/11576). This frequency is about 1469 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.00001), strong evidence that this is likely a benign polymorphism found primarily in the populations of Latino origin. The variant has been reported in patients and controls in the literature, without strong evidence for causality, and in some cases classified as a polymorphism/neutral. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
GeneDx	RCV000038105	SCV000725402	benign	not specified	2017-02-06	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.
Ambry Genetics	RCV000620878	SCV000735576	benign	Cardiovascular phenotype	2017-03-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Eurofins Ntd Llc (ga)	RCV000038105	SCV000859697	benign	not specified	2018-03-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777790	SCV000913774	benign	Cardiomyopathy	2018-10-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172546	SCV001159397	benign	not provided	2021-02-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777790	SCV004240545	benign	Cardiomyopathy	2022-07-21	criteria provided, single submitter	clinical testing