rs397516142
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM2PM5PP2BP4
The NM_000257.4(MYH7):c.2348G>T(p.Arg783Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R783H) has been classified as Pathogenic.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251466Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135906
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
This missense variant replaces arginine with leucine at codon 783 of the MYH7 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with sudden arrhythmic death (PMID: 26498160), in one individual affected with sudden cardiac death (PMID: 34984526), and in one individual affected with familial amyloid polyneuropathy and left ventricular hypertrophy who also carried a pathogenic variant in the TTR gene (PMID: 34817018). This variant has been identified in 2/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg783His and p.Arg783Pro, are considered to be disease-causing (ClinVar variation ID: 193999, 42895), suggesting that arginine at this position is important for MYH7 protein function. 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. -
This missense variant replaces arginine with leucine at codon 783 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251466 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. -
not provided Uncertain:2
Identified in a patient who died suddenly at 50 years of age and was found to have left ventricular hypertrophy (Fadoni et al., 2022); Identified in a patient with familial amyloid polyneuropathy who also harbored a pathogenic variant in the TTR gene (Rodrigues et al., 2021); 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, 34984526, 34817018, 29300372) -
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Hypertrophic cardiomyopathy Uncertain:1
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 783 of the MYH7 protein (p.Arg783Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or sudden cardiac death, clinical features of autosomal dominant MYH7-related myopathy (PMID: 34984526; internal data). ClinVar contains an entry for this variant (Variation ID: 454355). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. 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. 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. -
Cardiovascular phenotype Uncertain:1
The p.R783L variant (also known as c.2348G>T), located in coding exon 19 of the MYH7 gene, results from a G to T substitution at nucleotide position 2348. The arginine at codon 783 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in sudden death cohorts (Nunn LM et al. Europace, 2016 Jun;18:888-96; Fadoni J et al. Int J Legal Med, 2022 Mar;136:483-491). Two other alterations at the same codon, p.R783H (c.2348G>A) and p.R783P (c.2348G>C), have been detected in cardiomyopathy cohorts (Walsh R et al. Genet. Med., 2017 Feb;19:192-203). 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 amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at