ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1700G>A (p.Arg567His)

gnomAD frequency: 0.00001  dbSNP: rs377491278
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000035741 SCV001976475 uncertain significance Primary dilated cardiomyopathy 2021-09-27 reviewed by expert panel curation The c.1700G>A (p.Arg567His) variant in MYH7 has been identified in 3 individuals with DCM, 1 of whom also had an additional variant in another DCM-associated gene (PS4_Supporting; Pugh 2014 PMID:24503780; Walsh 2017 PMID:27532257; GeneDx pers. comm., LMM pers. comm.) and segregated with disease in 3 affected relatives with DCM from 1 family (PP1; LMM pers. comm.). Additionally, this variant has also been reported in an individual with neuropathy and unspecified heart disease who also had an additional variant in a gene that could account for the clinical features observed (Invitae pers. comm.). This variant has been identified in 0.003% (1/30616) of South Asian chromosomes (PM2;, v2.1.1). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore, PM1 is not applicable. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PP1; PM2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000035741 SCV000059392 likely pathogenic Primary dilated cardiomyopathy 2014-04-04 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV000799659 SCV000939333 uncertain significance Hypertrophic cardiomyopathy 2024-01-16 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 567 of the MYH7 protein (p.Arg567His). This variant is present in population databases (rs377491278, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 42860). 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 MYH7 protein function with a positive predictive value of 95%. 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.
GeneDx RCV003223608 SCV003919423 likely pathogenic not provided 2023-04-11 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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: 27532257, 31447099, 24503780, 29300372)
Ambry Genetics RCV003298054 SCV003993379 uncertain significance Cardiovascular phenotype 2023-06-04 criteria provided, single submitter clinical testing The p.R567H variant (also known as c.1700G>A), located in coding exon 14 of the MYH7 gene, results from a G to A substitution at nucleotide position 1700. The arginine at codon 567 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in individuals with dilated cardiomyopathy (DCM) with and without features of noncompaction, some of whom had variants in other cardiomyopathy-related genes, and was reported to segregate with disease in a family with DCM (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; external communication). This amino acid position is well 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003486554 SCV004239442 likely pathogenic Cardiomyopathy 2023-05-25 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV003223608 SCV005042491 uncertain significance not provided 2024-04-01 criteria provided, single submitter clinical testing

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