rs377461670
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP2PP3_Strong
The NM_000257.4(MYH7):c.5029C>T(p.Arg1677Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,888 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. R1677H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5029C>T | p.Arg1677Cys | missense_variant | 35/40 | ENST00000355349.4 | |
MHRT | NR_126491.1 | n.189G>A | non_coding_transcript_exon_variant | 2/6 | |||
MYH7 | NM_001407004.1 | c.5029C>T | p.Arg1677Cys | missense_variant | 34/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.5029C>T | p.Arg1677Cys | missense_variant | 35/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251376Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135874
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461888Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8AN XY: 727244
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 04, 2023 | This missense variant replaces arginine with cysteine at codon 1677 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant was also reported in one individual affected with dilated cardiomyopathy (PMID: 29773157). This variant has also been reported in compound heterozygous state with p.Gln44* in two siblings affected with left ventricular non-compaction cardiomyopathy (PMID: 30924982). Their parents were heterozygous carriers of either mutation and showed no clinical symptoms. This variant has been identified in 3/251376 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 | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 30, 2021 | - - |
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1677 of the MYH7 protein (p.Arg1677Cys). This variant is present in population databases (rs377461670, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of MYH7-related cardiomyopathy (PMID: 27532257, 30924982; Invitae). ClinVar contains an entry for this variant (Variation ID: 181270). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 14, 2021 | Variant summary: MYH7 c.5029C>T (p.Arg1677Cys) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251376 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5029C>T has been reported in the literature in individuals affected with Cardiomyopathy (Kolokotronis_2019, Walsh_2016, Ware_2018). These reports however, do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2020 | Reported in two children with left ventricular non-compaction cardiomyopathy who also had a novel MYH7 Q44X variant in trans, the parent harboring R1677C had mild septal hypertrophy (Kolokotronis et al., 2019) and in a patient referred for HCM genetic testing (Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 30924982, 21750094, 27532257) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 27, 2022 | The p.R1677C variant (also known as c.5029C>T), located in coding exon 33 of the MYH7 gene, results from a C to T substitution at nucleotide position 5029. The arginine at codon 1677 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in a patient referred for hypertrophic cardiomyopathy genetic testing; however, clinical details were limited (Walsh R et al. Genet Med. 2017;19:192-203). This variant has also been reported in a dilated cardiomyopathy (DCM) cohort (Ware JS et al. J Am Coll Cardiol, 2018 05;71:2293-2302). This alteration was also detected in siblings with left ventricular non-compaction (LVNC) who also carried a nonsense alteration in MYH7 (Kolokotronis K et al. Hum Mutat, 2019 08;40:1101-1114). Another variant affecting this codon (p.R1677H) has been reported in cardiomyopathy cohorts; however clinical details are limited (Waldmüller S et al. Eur J Heart Fail. 2011;13:1185-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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