rs397516171
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000257.4(MYH7):c.2788G>C(p.Glu930Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E930K) has been classified as Pathogenic.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Myosin storage myopathy Pathogenic:2
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not provided Pathogenic:2
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Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27247418, 18533079, 16858239, 27532257, 28606303, 21310275, 19134269, 29212898, 32746448, 34542152, 33906374, 29300372) -
Hypertrophic cardiomyopathy Pathogenic:2
proposed classification - variant undergoing re-assessment, contact laboratory -
This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 930 of the MYH7 protein (p.Glu930Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 27247418, 27532257; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164312). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. -
Dilated cardiomyopathy 1S Pathogenic:1
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Cardiomyopathy Pathogenic:1
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MYH7-related skeletal myopathy Pathogenic:1
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Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Pathogenic:1
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Myopathy, myosin storage, autosomal recessive Pathogenic:1
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MYH7-related disorder Pathogenic:1
The MYH7 c.2788G>C variant is predicted to result in the amino acid substitution p.Glu930Gln. This variant was reported in multiple individuals with hypertrophic cardiomyopathy and left ventricular noncompaction (Girolami et al. 2006. PubMed ID: 16858239; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Miller et al. 2017. PubMed ID: 29212898; Table S2, Burstein et al. 2021. PubMed ID: 32746448; Table S6, Park et al. 2022. PubMed ID: 34542152). This variant has not been reported in a large population database, indicating this variant is rare. A different nucleotide substitution affecting the same amino acid (p.Glu930Lys) has been reported in individuals with hypertrophic cardiomyopathy (Table S1B, Walsh et al. 2017. PubMed ID: 27532257). Taken together, the c.2788G>C (p.Glu930Gln) variant is interpreted as pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.E930Q variant (also known as c.2788G>C), located in coding exon 21 of the MYH7 gene, results from a G to C substitution at nucleotide position 2788. The glutamic acid at codon 930 is replaced by glutamine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (Girolami F et al. J Cardiovasc Med (Hagerstown), 2006 Aug;7:601-7; Olivotto I et al. Mayo Clin Proc, 2008 Jun;83:630-8; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Ware SM et al. J Am Heart Assoc, 2021 May;10:e017731; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476; Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Hypertrophic cardiomyopathy 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at