rs397516227
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000257.4(MYH7):c.4720C>T(p.Arg1574Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,836 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1574Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.4720C>T | p.Arg1574Trp | missense_variant | 34/40 | ENST00000355349.4 | |
MHRT | NR_126491.1 | n.498G>A | non_coding_transcript_exon_variant | 3/6 | |||
MYH7 | NM_001407004.1 | c.4720C>T | p.Arg1574Trp | missense_variant | 33/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.4720C>T | p.Arg1574Trp | missense_variant | 34/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461836Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727208
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 16, 2014 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 24, 2021 | Variant summary: MYH7 c.4720C>T (p.Arg1574Trp) 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 was absent in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4720C>T has been reported in the literature in individuals affected with Dilated cardiomyopathy (Pugh_2014, Walsh_2017). These reports 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1574 of the MYH7 protein (p.Arg1574Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular non-compaction (PMID: 24503780, 27532257, 33500567). ClinVar contains an entry for this variant (Variation ID: 43033). 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%. 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 14, 2019 | The p.R1574W variant (also known as c.4720C>T), located in coding exon 32 of the MYH7 gene, results from a C to T substitution at nucleotide position 4720. The arginine at codon 1574 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was reported in two individuals with dilated cardiomyopathy (DCM) (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8: Walsh R et al. Genet. Med., 2017 02;19:192-203). 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