ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3866G>A (p.Arg1289Gln)

gnomAD frequency: 0.00001  dbSNP: rs1287612987
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002363194 SCV002624785 uncertain significance Cardiovascular phenotype 2023-03-01 criteria provided, single submitter clinical testing The p.R1289Q variant (also known as c.3866G>A), located in coding exon 27 of the MYH7 gene, results from a G to A substitution at nucleotide position 3866. The arginine at codon 1289 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an individual with dilated cardiomyopathy (DCM), who was found to have an additional alteration in another cardiac-related gene (Kolokotronis K et al. J Clin Med, 2020 Jul;9:[ePub ahead of print]). 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 RCV002487879 SCV002784060 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 2021-08-21 criteria provided, single submitter clinical testing
Invitae RCV002536173 SCV002983344 uncertain significance Hypertrophic cardiomyopathy 2023-01-17 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 689588). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32659924). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1289 of the MYH7 protein (p.Arg1289Gln).
GeneDx RCV003320763 SCV004025786 uncertain significance not provided 2023-02-13 criteria provided, single submitter clinical testing Reported in an individual with DCM who also has a variant in the RBM20 gene (Kolokotronis et al., 2020); 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: 34542152, 32659924)
All of Us Research Program, National Institutes of Health RCV004002903 SCV004833737 uncertain significance Cardiomyopathy 2023-05-04 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 1289 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 dilated cardiomyopathy (PMID: 32659924). This variant has been identified in 3/282870 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.
Institute of Human Genetics, University of Wuerzburg RCV000850345 SCV000992521 uncertain significance Primary dilated cardiomyopathy no assertion criteria provided clinical testing

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