ClinVar Miner

Submissions for variant NM_001927.4(DES):c.665G>A (p.Arg222His)

gnomAD frequency: 0.00011  dbSNP: rs367961979
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154697 SCV000204376 uncertain significance not specified 2013-04-12 criteria provided, single submitter clinical testing The Arg222His variant in DES has not been reported in individuals with cardiomyo pathy or in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide st rong support for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of this variant.
Illumina Laboratory Services, Illumina RCV000540698 SCV000427702 likely benign Desmin-related myofibrillar myopathy 2017-04-27 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 RCV000260200 SCV000427703 likely benign Dilated cardiomyopathy 1I 2017-04-27 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.
Illumina Laboratory Services, Illumina RCV000324508 SCV000427704 likely benign Neurogenic scapuloperoneal syndrome, Kaeser type 2017-04-27 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 RCV000379116 SCV000427705 likely benign Myofibrillar Myopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000540698 SCV000654178 uncertain significance Desmin-related myofibrillar myopathy 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 222 of the DES protein (p.Arg222His). This variant is present in population databases (rs367961979, gnomAD 0.1%). This missense change has been observed in individual(s) with DES-related conditions (PMID: 25928149, 28416588, 32150461). ClinVar contains an entry for this variant (Variation ID: 178016). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DES protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc RCV001657879 SCV001879788 uncertain significance not provided 2021-04-28 criteria provided, single submitter clinical testing
GeneDx RCV001657879 SCV002498850 uncertain significance not provided 2022-11-07 criteria provided, single submitter clinical testing Has been reported in association with DCM and HCM in published literature; however, a second cardiogenetic variant was identified in most cases (Dal Ferro et al., 2017; Hoss et al., 2020; Truszkowska et al., 2015; Cohen et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25928149, 28416588, 32150461, 33652119)
Ambry Genetics RCV002362813 SCV002663275 benign Cardiovascular phenotype 2021-09-20 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.
Revvity Omics, Revvity Omics RCV001657879 SCV003829040 uncertain significance not provided 2023-03-28 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001657879 SCV001931125 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001657879 SCV001952783 likely benign not provided no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV003483525 SCV004228685 not provided Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 05-08-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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