Submissions for variant NM_002471.4(MYH6):c.4136C>T (p.Thr1379Met)

gnomAD frequency: 0.00036  dbSNP: rs145611185

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216382	SCV000272024	uncertain significance	not specified	2015-08-06	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000989182	SCV000287422	likely benign	Hypertrophic cardiomyopathy 14	2024-01-19	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000216382	SCV000740618	likely benign	not specified	2016-11-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000989182	SCV001139403	benign	Hypertrophic cardiomyopathy 14	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000233729	SCV001149134	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	MYH6: PP3, BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171183	SCV001333875	benign	Cardiomyopathy	2017-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216382	SCV001360445	benign	not specified	2019-01-28	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000233729	SCV001820912	likely benign	not provided	2020-09-01	criteria provided, single submitter	clinical testing	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)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000233729	SCV002049100	likely benign	not provided	2020-11-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326893	SCV002628904	likely benign	Cardiovascular phenotype	2019-09-16	criteria provided, single submitter	clinical testing	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.
Blueprint Genetics	RCV000157339	SCV000207076	uncertain significance	Primary familial hypertrophic cardiomyopathy	2013-12-20	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000233729	SCV001741349	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000233729	SCV001917965	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000233729	SCV001928079	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000233729	SCV001951783	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000233729	SCV001970279	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734747	SCV005355600	uncertain significance	MYH6-related disorder	2024-05-13	no assertion criteria provided	clinical testing	The MYH6 c.4136C>T variant is predicted to result in the amino acid substitution p.Thr1379Met. This variant has been reported in two unrelated individuals with hypoplastic left heart that carried a second MYH6 variant in the compound heterozygous state (Theis et al. 2015. PubMed ID: 26085007; Theis et al. 2020. PubMed ID: 33325730). Additionally, this variant has been reported in an individual with hypoplastic left heart; however, the variant’s zygosity is unclear (Preuss et al. 2016. PubMed ID: 27760138). Additionally, this variant was found in the heterozygous state in two individuals with hypoplastic left heart syndrome (Tomita-Mitchell et al. 2016. PubMed ID: 27789736). This variant has also been reported in individuals with congenital heart defects (Table S1, Posch et al. 2011. PubMed ID: 22194935; Blue et al. 2014. PubMed ID: 25500235; Table S2, Jia et al. 2015. PubMed ID: 25931334), dilated/hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia (Table S2, van Lint et al. 2019. PubMed ID: 30847666; Table S1, Lopes et al. 2014. PubMed ID: 25351510; Table S4, Verdonschot et al. 2020. PubMed ID: 32880476), Brugada syndrome (Hertz et al. 2014. PubMed ID: 25467552), and mitral valve prolapse (Table S2, van Wijngaarden et al. 2020. PubMed ID: 32277046). However, in several of these cases the variant either failed to segregate with disease or another pathogenic variant was identified (Blue et al. 2014. PubMed ID: 25500235; Table S2, Jia et al. 2015. PubMed ID: 25931334). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/180425/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.