rs121913653
Variant summary
Our verdict is Benign. Variant got -6 ACMG points: 2P and 8B. PM1BA1
This summary comes from the ClinGen Evidence Repository: The c.1322C>T (p.Thr441Met) in MYH7 has been identified in 0.2% (FAF 95% CI; 47/18394) of East Asian chromosomes in gnomAD (BA1; https://gnomad.broadinstitute.org). While this variant lies in the head region of the protein (aa 181-937), where missense variants are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257), this is not considered to be in conflict with BA1 since benign variation within this region was considered during that analysis. In summary, this variant meets criteria to be is classified as benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BA1, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA010543/MONDO:0004994/002
Frequency
Consequence
ENST00000355349.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.1322C>T | p.Thr441Met | missense_variant | 14/40 | ENST00000355349.4 | NP_000248.2 | |
MYH7 | NM_001407004.1 | c.1322C>T | p.Thr441Met | missense_variant | 13/39 | NP_001393933.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.1322C>T | p.Thr441Met | missense_variant | 14/40 | 1 | NM_000257.4 | ENSP00000347507 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000235 AC: 59AN: 251494Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135920
GnomAD4 exome AF: 0.0000664 AC: 97AN: 1461894Hom.: 0 Cov.: 33 AF XY: 0.0000674 AC XY: 49AN XY: 727248
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74338
ClinVar
Submissions by phenotype
Cardiomyopathy Benign:4
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 26, 2023 | - - |
Benign, reviewed by expert panel | curation | ClinGen Cardiomyopathy Variant Curation Expert Panel | Jun 16, 2021 | The c.1322C>T (p.Thr441Met) in MYH7 has been identified in 0.2% (FAF 95% CI; 47/18394) of East Asian chromosomes in gnomAD (BA1; https://gnomad.broadinstitute.org). While this variant lies in the head region of the protein (aa 181-937), where missense variants are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257), this is not considered to be in conflict with BA1 since benign variation within this region was considered during that analysis. In summary, this variant meets criteria to be classified as benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BA1, PM1. - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 11, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 03, 2018 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 08, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 12, 2016 | The T441M variant in the MYH7 gene has been reported previously in one child with skeletal myopathy with mild atrial enlargement and septal thickness in the 95th percentile and was absent in 200 control chromosomes (Darin et al., 2007). Expression studies showed that mutated and wild-type alleles were equally expressed at the mRNA level (Darin et al., 2007). The T441M variant has also been reported in one Chinese family with hypertrophic cardiomyopathy (Fan et al., 2011; Feng et al., 2011). The T441M variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The T441M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position in the myosin motor domain that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (N437D, M439T, M439R, V440M, R442C, R442H, I443T, N444S) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret T441M as a variant of uncertain significance, which may be related to the muscle weakness and atrophy reported in this individual. - |
MYH7-related skeletal myopathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 05, 2007 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 30, 2017 | MYH7 1322C>T: Disclaimer: This variant has not undergone a full assessment. The following are preliminary notes: Classified as VUS3 in 2014 and no new pubs sin ce then. Has a max MAF in ExAC of 0.15% (13 alleles) and gnomad of 0.27% (53 al leles) - frequency too high for disease. - |
Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 05, 2021 | - - |
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 24, 2023 | - - |
Hypertrophic cardiomyopathy 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at