Submissions for variant NM_004415.4(DSP):c.4065T>C (p.Tyr1355=)

gnomAD frequency: 0.00073  dbSNP: rs148478829

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038034	SCV000061700	benign	not specified	2018-04-04	criteria provided, single submitter	clinical testing	Tyr1355Tyr in exon 23 of DSP: This variant is classified as benign because it d oes not alter an amino acid residue and is not located within the splice consens us sequence. Computational tools do not predict an impact on splicing. It has b een identified in 0.1% (158/126102) of European chromosomes by the Genome Aggreg ation Databsae (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148478829). AC MG/AMP Criteria applied: BA1; BP4; BP7.
Ambry Genetics	RCV000253751	SCV000319584	likely benign	Cardiovascular phenotype	2015-05-07	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.
Illumina Laboratory Services, Illumina	RCV000269608	SCV000465018	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000327042	SCV000465019	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000291041	SCV000465021	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086611	SCV000555751	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771828	SCV000904540	likely benign	Cardiomyopathy	2018-06-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038034	SCV000917312	benign	not specified	2018-11-23	criteria provided, single submitter	clinical testing	Variant summary: DSP c.4065T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00083 in 276350 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 80 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4065T>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000463312	SCV001154641	likely benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing	DSP: BP4, BP7
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771828	SCV004240528	benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996340	SCV004814966	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-02-05	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000463312	SCV001740920	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038034	SCV001920210	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000038034	SCV001931031	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038034	SCV001955097	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000463312	SCV001966936	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924923	SCV004741839	likely benign	DSP-related disorder	2019-05-28	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).