rs28933098
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_000257.4(MYH7):c.5533C>T(p.Arg1845Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,642 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. R1845Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.5533C>T | p.Arg1845Trp | missense_variant | 37/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.5533C>T | p.Arg1845Trp | missense_variant | 36/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.5533C>T | p.Arg1845Trp | missense_variant | 37/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1457642Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 725400
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Myosin storage myopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Oct 19, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 14, 2009 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 26, 2022 | - - |
Hyaline body myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 24, 2020 | The p.Arg1845Trp variant in MYH7 has been reported in at least 10 individuals with myosin storage myopathy and segregated with disease in at least 10 affected family members from at least three families (Tajsharghi 2003, Laing 2005, Shingde 2006, Pegoraro 2007, Kiphuth 2010, Harris 2017, Li 2018). This variant was absent from large population studies, but has been reported in ClinVar (Variation ID: 14114). Computational prediction tools and conservation analyses are consistent with pathogenicity. In vitro and in vivo functional studies support an impact on protein function (Armel 2009, Dahl-Halvarsson 2017, Viswanathan 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant myosin storage myopathy. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate, PP3. - |
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 31, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MYH7 function (PMID: 19336582). 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: 14114). This missense change has been observed in individuals with myosin storage myopathy and skeletal myopathy (PMID: 14520662, 15699387, 17118657, 17336526, 20376763). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1845 of the MYH7 protein (p.Arg1845Trp). - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 08, 2022 | This missense variant replaces arginine with tryptophan at codon 1845 in the LMM domain 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). Functional studies have shown that this variant disrupts myosin filament assembly (PMID: 19336582, 28125727, 28973424) and impairs jump and flight ability in Drosophila mutants (PMID: 28973424, 33234710). This variant has been reported in multiple families and individuals affected with myosin-related disorders without cardiac involvement, including myosin storage myopathy (PMID: 14520662, 15699387, 17118657, 17336526, 20376763), scapulo-peroneal myopathy (PMID: 17336526), hereditary myopathy (PMID: 29170849), and inherited muscle disease (PMID: 31791368). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In summary, while this variant has been reported to cause myosin storage myopathy, the additional evidence is insufficient to determine the role of this variant in cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at