ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.4822C>T (p.Arg1608Cys)

gnomAD frequency: 0.00004  dbSNP: rs201683868
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000172020 SCV000050995 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV000465595 SCV000546136 uncertain significance Hypertrophic cardiomyopathy 14 2023-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1608 of the MYH6 protein (p.Arg1608Cys). This variant is present in population databases (rs201683868, gnomAD 0.01%). This missense change has been observed in individual(s) with ventricular septal defect (PMID: 29332214). ClinVar contains an entry for this variant (Variation ID: 191710). 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 MYH6 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000172020 SCV001474099 uncertain significance not provided 2020-03-12 criteria provided, single submitter clinical testing The MYH6 c.4822C>T; p.Arg1608Cys variant (rs201683868) is reported in the literature in an individual affected with ventricular septal defect, although its clinical significance in this patient was not demonstrated (Pulignani 2018). This variant is found in the general population with an overall allele frequency of 0.004% (10/282862 alleles) in the Genome Aggregation Database. The arginine at codon 1608 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Arg1608Cys variant is uncertain at this time. References: Pulignani S et al. Targeted Next-Generation Sequencing in Patients with Non-syndromic Congenital Heart Disease. Pediatr Cardiol. 2018 Apr;39(4):682-689.
GeneDx RCV000172020 SCV001793772 uncertain significance not provided 2024-03-22 criteria provided, single submitter clinical testing Has not been published in association with cardiomyopathy to our knowledge, but has been reported in one individual with a ventricular septal defect, and one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia or family history of sudden cardiac death who underwent exome sequencing (PMID: 29332214, 23861362); 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: 23861362, 34426522, 35621855, 29332214)
Ambry Genetics RCV002336409 SCV002635055 uncertain significance Cardiovascular phenotype 2023-01-06 criteria provided, single submitter clinical testing The p.R1608C variant (also known as c.4822C>T), located in coding exon 31 of the MYH6 gene, results from a C to T substitution at nucleotide position 4822. The arginine at codon 1608 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in an individual with a ventricular septal defect (Pulignani S et al. Pediatr Cardiol, 2018 Apr;39:682-689). This alteration has also been reported as a secondary cardiac variant in an exome cohort and was detected on genome sequencing in a cohort not selected for the presence of cardiovascular disease; however, details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Kars ME et al. Proc Natl Acad Sci U S A. 2021 Sep;118(36)). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002492719 SCV002792739 uncertain significance Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to 2021-10-21 criteria provided, single submitter clinical testing

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