ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5065C>T (p.Arg1689Cys)

gnomAD frequency: 0.00001  dbSNP: rs730880915
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001721011 SCV000208805 uncertain significance not provided 2021-03-18 criteria provided, single submitter clinical testing Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID 181394; Landrum et al., 2016); 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: 32163302)
Labcorp Genetics (formerly Invitae), Labcorp RCV000693933 SCV000822356 uncertain significance Hypertrophic cardiomyopathy 2022-06-05 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 1689 of the MYH7 protein (p.Arg1689Cys). This variant is present in population databases (rs730880915, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181394). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). 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.
Color Diagnostics, LLC DBA Color Health RCV001185248 SCV001351421 uncertain significance Cardiomyopathy 2023-03-09 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 1689 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 32163302, 33495597). This variant has been identified in 6/282678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002478480 SCV002790918 uncertain significance Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy 2022-02-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV003372630 SCV004083060 uncertain significance Cardiovascular phenotype 2023-08-18 criteria provided, single submitter clinical testing The p.R1689C variant (also known as c.5065C>T), located in coding exon 33 of the MYH7 gene, results from a C to T substitution at nucleotide position 5065. The arginine at codon 1689 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with an MYBPC3 variant in an individual from a hypertrophic cardiomyopathy cohort (Harper AR et al. Circ Genom Precis Med, 2020 Jun;13:e002783). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV001185248 SCV004816590 uncertain significance Cardiomyopathy 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 1689 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 32163302, 33495597). This variant has been identified in 6/282678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004586578 SCV005076069 uncertain significance not specified 2024-04-26 criteria provided, single submitter clinical testing Variant summary: MYH7 c.5065C>T (p.Arg1689Cys) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251312 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5065C>T has been reported in the literature as a VUS in an individual affected with hypertrophic cardiomyopathy who carried an additional MYBPC3 variant (e.g. Harper_2020). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32163302). ClinVar contains an entry for this variant (Variation ID: 181394). Based on the evidence outlined above, the variant was classified as uncertain significance.

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