Submissions for variant NM_004415.4(DSP):c.2723G>A (p.Arg908His)

gnomAD frequency: 0.00041  dbSNP: rs142494121

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172535	SCV000051384	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154408	SCV000204076	uncertain significance	not specified	2013-11-26	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Arg908His varia nt in DSP has been reported in 2 individuals with ARVC, but did not segregate wi th clinical features of ARVC in 1 relative (Quarta 2011). In addition, this vari ant has now been identified by our laboratory 5 individuals with various clinica l features (1 with RCM, 1 with LVH and RV dyskinesis, 1 with ARVC, 1 with LVNC and 1 with DCM and LVNC). It has also been identified in 0.2% (13/8600) of Europ ean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS/; dbSNP rs142494121). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide s trong support for or against an impact to the protein. In summary, the frequency of this variant and the presence in such variable phenotypes suggest that this variant is more likely benign, but additional information is needed to establish this with confidence.
GeneDx	RCV000154408	SCV000233597	benign	not specified	2018-02-07	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000172535	SCV000281164	likely benign	not provided	2015-06-19	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Illumina Laboratory Services, Illumina	RCV000300911	SCV000464950	likely benign	Woolly hair-skin fragility syndrome	2018-09-12	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	RCV000275053	SCV000464952	likely benign	Lethal acantholytic epidermolysis bullosa	2018-09-12	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	RCV000330101	SCV000464953	likely benign	Arrhythmogenic right ventricular dysplasia 8	2018-09-12	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae	RCV001083035	SCV000555742	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619767	SCV000736486	benign	Cardiovascular phenotype	2018-08-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000771121	SCV000902840	likely benign	Cardiomyopathy	2018-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154408	SCV000917309	benign	not specified	2018-10-08	criteria provided, single submitter	clinical testing	Variant summary: DSP c.2723G>A (p.Arg908His) results in a non-conservative amino acid change located in the Spectrin/alpha-actinin domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 277668 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 107-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.2723G>A has been reported in the literature in individuals affected with Arrhythmia (Quarta_2011, Haas_2015, Ng_2013, Nunn_2016) including one family that showed lack of cosegregation with disease (Quarta_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign (4x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000172535	SCV001154636	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	DSP: BP4, BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771121	SCV001333764	benign	Cardiomyopathy	2017-12-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172535	SCV004564758	likely benign	not provided	2023-09-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907460	SCV004732203	likely benign	DSP-related condition	2020-10-15	criteria provided, single submitter	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).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172535	SCV001742284	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000154408	SCV001919829	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172535	SCV001926710	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000154408	SCV001955346	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172535	SCV001972021	likely benign	not provided		no assertion criteria provided	clinical testing