ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4772T>A (p.Leu1591Gln)

gnomAD frequency: 0.00004  dbSNP: rs730880808
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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 RCV000619034 SCV000736365 uncertain significance Cardiovascular phenotype 2021-12-27 criteria provided, single submitter clinical testing The p.L1591Q variant (also known as c.4772T>A), located in coding exon 32 of the MYH7 gene, results from a T to A substitution at nucleotide position 4772. The leucine at codon 1591 is replaced by glutamine, an amino acid with dissimilar properties. This alteration has been reported in at least two cases of sudden cardiac death and has been seen in at least one hypertrophic cardiomyopathy (HCM) cohort (Campuzano O et al. Front Genet, 2019 May; Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230; 10:450; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Campuzano O et al. J. Am. Coll. Cardiol., 2015 Dec;66:2913-2914; Campuzano O et al. Forensic Sci Int, 2014 12;245:30-7). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000778015 SCV000914125 uncertain significance Cardiomyopathy 2022-11-21 criteria provided, single submitter clinical testing This missense variant replaces leucine with glutamine at codon 1591 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden cardiac death and myocarditis (PMID 25447171). This individual and six relatives diagnosed with arrhythmogenic cardiomyopathy all carried a pathogenic truncation variant in the PKP2 gene that could explain the observed phenotype in this family (PMID: 31156706). This variant has been identified in 10/251476 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.
Invitae RCV001211825 SCV001383384 uncertain significance Hypertrophic cardiomyopathy 2022-09-12 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1591 of the MYH7 protein (p.Leu1591Gln). This variant is present in population databases (rs730880808, gnomAD 0.007%). This missense change has been observed in individual(s) with Laing distal myopathy (PMID: 22918376). ClinVar contains an entry for this variant (Variation ID: 181265). 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 not expected to disrupt MYH7 protein function. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000778015 SCV002042687 uncertain significance Cardiomyopathy 2020-12-21 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002498788 SCV002812769 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 2021-09-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003133156 SCV003817732 uncertain significance not provided 2022-03-07 criteria provided, single submitter clinical testing

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