Submissions for variant NM_000257.4(MYH7):c.1046T>C (p.Met349Thr)

gnomAD frequency: 0.00002  dbSNP: rs121913640

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000694881	SCV001842662	uncertain significance	Hypertrophic cardiomyopathy	2021-06-16	reviewed by expert panel	curation	The c.1046T>C (p.Met349Thr) variant in MYH7 has been reported in at least 6 individuals with HCM (PS4_Supporting; Jeschke 1998 PMID:9544842; GeneDx: pers comm., Ambry: pers comm, Invitae: pers comm), 1 of whom also had additional variants in other HCM-associated genes (Ambry pers comm;). Additionally, one of these individuals also had severe, early-onset (<20 yo) presentation of HCM and carried a second de novo MYH7 variant on the second allele that was classified as pathogenic by this expert panel (p.Arg719Trp, ClinVar variation ID:14104). This variant has also been reported in 1 individual with unspecified heart disease, 1 with LVH, and 1 with arrhythmia, and 1 with LVNC with atrial and ventricular septal defect (Ambry pers comm.; GeneDX pers comm.; Invitae pers comm.; OMGL pers comm.). This variant has also been identified in 0.007% (1/15378) of European chromosomes, in gnomAD (v2.1.1; http://gnomad.broadinstitute.org). This represents only a fraction of the total European chromosomes, suggesting low coverage at this locus. Therefore, data from large population studies are insufficient to assess the frequency of this variant and apply PM2. Additionally, since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM1.
GeneDx	RCV000127019	SCV000170552	uncertain significance	not provided	2021-10-01	criteria provided, single submitter	clinical testing	Reported previously in one individual with HCM who also harbored another de novo MYH7 variant on the opposite allele; he M349T variant was maternally inherited and was identified in several other relatives, all of whom were asymptomatic (Jeschke et al., 1998); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#14094; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 9544842, 10900182, 15737656, 18761664, 26272908, 21310275, 11968089)
Ambry Genetics	RCV000621114	SCV000736690	uncertain significance	Cardiovascular phenotype	2019-12-03	criteria provided, single submitter	clinical testing	The c.1046T>C (p.M349T) alteration is located in exon 12 (coding exon 10) of the MYH7 gene. This alteration results from a T to C substitution at nucleotide position 1046, causing the methionine (M) at amino acid position 349 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694881	SCV000823346	uncertain significance	Hypertrophic cardiomyopathy	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 349 of the MYH7 protein (p.Met349Thr). This variant is present in population databases (rs121913640, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) and an early onset form of HCM (PMID: 9544842, 18761664, 32894683). ClinVar contains an entry for this variant (Variation ID: 14094). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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.
Color Diagnostics, LLC DBA Color Health	RCV001188427	SCV001355485	uncertain significance	Cardiomyopathy	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 349 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 9544842, 18761664, 24793961, 32894683). In one family, this variant was reported in compound heterozygous state with another de novo pathogenic MYH7 variant in an individual affected with early-onset hypertrophic cardiomyopathy (PMID: 9544842, 18761664). 6 relatives of this individual were asymptomatic heterozygous carriers for this variant. This variant has been identified in 1/31328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002490370	SCV002786504	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2022-02-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001188427	SCV004822523	uncertain significance	Cardiomyopathy	2024-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 349 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 9544842, 18761664, 24793961, 32894683). In one family, this variant was reported in compound heterozygous state with another de novo pathogenic MYH7 variant in an individual affected with early-onset hypertrophic cardiomyopathy (PMID: 9544842, 18761664). 6 relatives of this individual were asymptomatic heterozygous carriers for this variant. This variant has been identified in 1/31328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Molecular Genetics Laboratory, Motol Hospital	RCV000015150	SCV005620001	likely pathogenic	Hypertrophic cardiomyopathy 1	2025-01-08	criteria provided, single submitter	clinical testing	For KCNH2-related disorder appeared in affected cases while extremely rare in population (PM2 met), and the prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (PS4), missense variant located in a mutational hotspot (PM1), rare variant not present in gnomAD population (v4.1.0) (PM2), in silico prediction tools support the deleterious effect of this missense variant on the protein (PP3), reputable source reports this variant as pathogenic without laboratory evidence (PP5); detected in a proband with cardiac arrest and after the successful cardiopulmonary resuscitation; ACMG PS4, PM1, PM2, PP3, PP5
OMIM	RCV000015150	SCV000035407	pathogenic	Hypertrophic cardiomyopathy 1	1998-03-01	no assertion criteria provided	literature only