rs145611185
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BP6BS2
The NM_002471.4(MYH6):c.4136C>T(p.Thr1379Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,613,670 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1379T) has been classified as Likely benign.
Frequency
Consequence
NM_002471.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH6 | NM_002471.4 | c.4136C>T | p.Thr1379Met | missense_variant | 29/39 | ENST00000405093.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH6 | ENST00000405093.9 | c.4136C>T | p.Thr1379Met | missense_variant | 29/39 | 5 | NM_002471.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000322 AC: 49AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000581 AC: 146AN: 251472Hom.: 0 AF XY: 0.000581 AC XY: 79AN XY: 135920
GnomAD4 exome AF: 0.000912 AC: 1333AN: 1461448Hom.: 2 Cov.: 32 AF XY: 0.000876 AC XY: 637AN XY: 727034
GnomAD4 genome AF: 0.000322 AC: 49AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74376
ClinVar
Submissions by phenotype
not provided Benign:7
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 01, 2020 | Observed in a family with CHD; however, a nonsense variant in the TBX5 gene was also identified and was found to segregate with disease in this family, while the T1379M variant did not segregate with disease (Blue et al., 2014); Identified in an individual with Brugada syndrome (Hertz et al., 2016); Published in association with autosomal recessive pattern of inheritance in the literature after identifying the T1379M variant in an individual with hypoplastic left heart syndrome who harbored another variant on the opposite MYH6 allele (in trans) (Theis et al. 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar with conflicting classfications (ClinVar Variant ID 180425; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32880476, 32277046, 30847666, 27789736, 27760138, 26085007, 25500235, 20656787, 25467552) - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 18, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not specified Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 28, 2019 | Variant summary: MYH6 c.4136C>T (p.Thr1379Met) results in a non-conservative amino acid change located in the Myosin tail domain 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 0.00056 in 277218 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 44 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH6 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4136C>T has been reported in the literature in affected individuals (Preuss_2016, Tomita-Mitchell_2016, Hertz_2015, Jia_2015, Theis_2015, Blue_2014, Posch_2011) without strong evidence of causality while, it was documented to not co-segregate with disease (Theis_2015, Blue_2014). Furthermore, it was identified in at-least two families with congenital heart defects where an alternate molecular basis of disease, namely segregating mutations in the TBX5 gene, causative of Holt-Oram syndrome were identified (Blue_2014, Jia_2015). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (2x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 06, 2015 | The p.Thr1379Met variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (72/66714) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs145611185). Computational prediction tools and conservation analysis suggest that the p.Thr1379Met variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. In summary, the clin ical significance of the p.Thr1379Met variant is uncertain. - |
Likely benign, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Nov 25, 2016 | - - |
Hypertrophic cardiomyopathy 14 Benign:2
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Dec 20, 2013 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 01, 2017 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at