rs727503258
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP2PP3_ModeratePP5
The NM_000257.4(MYH7):c.2347C>T(p.Arg783Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R783H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.2347C>T | p.Arg783Cys | missense_variant | 21/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.2347C>T | p.Arg783Cys | missense_variant | 20/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.2347C>T | p.Arg783Cys | missense_variant | 21/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251474Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 03, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg783 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21211974). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 181182). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418). This variant is present in population databases (rs727503258, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 783 of the MYH7 protein (p.Arg783Cys). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Arg783Cys variant in MYH7 has been identified in 1 individual with HCM (Homburger 2016). It has been identified in 1/113752 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar (Variation ID: 181182). Computational prediction tools and conservation analysis suggest that the p.Arg783His variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In addition, 2 other variants involving this codon, p.Arg783His and p.Arg783Pro, have been identified in individuals with cardiomyopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PM5, PP3. - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 10, 2023 | Reported in association with HCM in published literature; however, detailed clinical information was not provided (Homburger et al., 2016; Bonaventure et al., 2019); 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: 31589614, 34135346, 27532257, 29300372, 27247418, 31110529, 30275503) - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 08, 2023 | This missense variant replaces arginine with cysteine at codon 783 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 individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 31110529). Different variants affecting the same codon, p.Arg783His and p.Arg783Pro, are considered to be disease-causing (ClinVar variation ID: 180437 and 42895), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 1/251474 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 02, 2023 | This missense variant replaces arginine with cysteine at codon 783 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 individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 31110529). Different variants affecting the same codon, p.Arg783His and p.Arg783Pro, are considered to be disease-causing (ClinVar variation ID: 180437 and 42895), suggesting that arginine at this position is important for MYH7 protein function. This variant has been identified in 1/251474 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 04, 2024 | The p.R783C variant (also known as c.2347C>T), located in coding exon 19 of the MYH7 gene, results from a C to T substitution at nucleotide position 2347. The arginine at codon 783 is replaced by cysteine, an amino acid with highly dissimilar 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 variant has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 Jun;113:6701-6; Robert-Paganin J et al. Nat Commun, 2018 Oct;9:4019; Bonaventura J et al. Arch Med Sci, 2019 May;15:641-649; Bonaventura J et al. J Am Heart Assoc, 2024 May;13:e033565). Another variant at the same codon, p.R783H (c.2348G>A), has been detected in numerous individual from hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing (Waldmüller S et al. Clin. Chem., 2008 Apr;54:682-7; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart, 2015 Feb;101:294-301; Jääskeläinen P et al. ESC Heart Fail. 2019 Apr;6(2):436-445; Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298; Hathaway J et al. BMC Cardiovasc Disord. 2021 03;21(1):126; Phan PD et al. JRSM Cardiovasc Dis. 2024 Jan;13:20480040231220100; Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at