Submissions for variant NM_004415.4(DSP):c.6881C>G (p.Ala2294Gly)

gnomAD frequency: 0.00062  dbSNP: rs147000526

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171919	SCV000050925	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038079	SCV000061745	uncertain significance	not specified	2017-01-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
CSER _CC_NCGL, University of Washington	RCV000148480	SCV000190182	likely benign	Arrhythmogenic right ventricular cardiomyopathy	2015-12-01	criteria provided, single submitter	research
GeneDx	RCV000171919	SCV000233642	likely benign	not provided	2021-01-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25637381, 25820315, 26314686, 27153395, 23299917, 25616645, 26498160, 23861362, 25163546, 25351510, 26899768, 27896284, 21859740, 26220970)
Illumina Laboratory Services, Illumina	RCV001095181	SCV000465178	likely benign	Arrhythmogenic right ventricular dysplasia 8	2019-05-16	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	RCV000297547	SCV000465179	likely benign	Lethal acantholytic epidermolysis bullosa	2019-05-16	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	RCV000267252	SCV000465181	likely benign	Woolly hair-skin fragility syndrome	2019-05-16	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	RCV001079594	SCV000555787	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621753	SCV000734930	likely benign	Cardiovascular phenotype	2019-01-17	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000148480	SCV000740334	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2017-01-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769239	SCV000900615	benign	Cardiomyopathy	2021-09-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769239	SCV000913763	likely benign	Cardiomyopathy	2018-09-18	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000769239	SCV000995751	likely benign	Cardiomyopathy	2019-01-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000171919	SCV001473395	likely benign	not provided	2019-11-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806031	SCV005429025	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-09-23	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000038079	SCV000280095	uncertain significance	not specified	2013-11-26	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of segregation in multiple cases we consider this variant a variant of uncertain significance, probably benign. The variant has been seen in at least 2 unrelated cases of DCM and 4 cases ARVC with failure to segregate in at least 4 cases. At least 7% of patients with autosomal dominant ARVC have been reported to have a mutation in the DSP gene (McNally E et al., 2009). The Ala2294Gly variant has been reported previously in two individuals with dilated cardiomyoapthy (Garcia-Pavia P et al., 2011). One of the probands was a 60 year old male, the other a 51 year old male. No segregation analysis was available. This was a cohort of 95 patients randomly selected from a cohort of 187 patients transplanted for DCM between 1993 and 2007. The authors did sequencing for plakophillin-2 (PKP2), desmoplakin (DSP), desmocollin-2 (DSC2), desmoglein (DSG2) and plakoglobin (JUP). They did not study other DCM genes. Garcia and Monserrat (2010, case presentation) reported this variant was identified in a proband with right ventricular dysfunction, whose father was also affected, but did not carry the variant. The proband carried three other variants in the tested ARVC genes. As part of the authors' review of this variant, they report this variant has been reported in an additional three families (Dr. Van der Zwaag, personal communication). In one of these families, a proband with ARVC had solely this variant and it failed to segregate with disease in the proband's mother who also had a clinical diagnosis of ARVC. Another family, the proband (72 years old) carried a second confirmed pathogenic mutation in DSP. In the third family, the variant was identified in the father of a male patient who died suddenly at age 25, although the patient did not have the variant and both were carrier of a confirmed pathogenic mutation in another gene. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The alanine at codon 2294 is conserved across species, as are neighboring amino acids. In total the variant has been seen in 3/6703 laboratory controls, published controls and individuals from publicly available population datasets. The variant was reported online in 3 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of 1/30/14). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. This variant is listed in dbSNP: rs147000526. The variant was not observed in the following laboratory and published control samples: Not present in 200 control individuals (Garcia-Pavia P e al., 2011)
Clinical Genetics, Academic Medical Center	RCV000171919	SCV001921298	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000171919	SCV001931157	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000171919	SCV001951722	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000171919	SCV001972329	likely benign	not provided		no assertion criteria provided	clinical testing