ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.2723G>A (p.Arg908His) (rs142494121)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619767 SCV000736486 uncertain significance Cardiovascular phenotype 2017-12-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172535 SCV000051384 likely benign not provided 2013-06-24 criteria provided, single submitter research
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.
Color RCV000771121 SCV000902840 likely benign Cardiomyopathy 2018-03-16 criteria provided, single submitter clinical testing
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.
Illumina Clinical Services Laboratory,Illumina RCV000300911 SCV000464950 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000355765 SCV000464951 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000275053 SCV000464952 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000330101 SCV000464953 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000460350 SCV000555742 likely benign Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-01-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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.

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