Submissions for variant NM_000258.3(MYL3):c.136T>C (p.Phe46Leu)

gnomAD frequency: 0.00002  dbSNP: rs730880953

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158936	SCV000208871	uncertain significance	not provided	2017-04-04	criteria provided, single submitter	clinical testing	The F46L variant has not been published as a mutation or as a benign polymorphism to our knowledge. The F46L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations in MYL3 are rare in HCM, and have been reported in only about 1% of patients with an autosomal dominant familial form of the disease (Cirino A et al., 2011). Another missense mutation in a nearby residue (E56G) has been reported in association with HCM, supporting the functional importance of this region of the protein. However, the F46L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Although this substitution occurs at a position that is conserved in mammals, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY,HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056549	SCV001220999	uncertain significance	Hypertrophic cardiomyopathy	2024-07-08	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 46 of the MYL3 protein (p.Phe46Leu). This variant is present in population databases (rs730880953, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 37652022). ClinVar contains an entry for this variant (Variation ID: 181437). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV001176079	SCV001339917	uncertain significance	Cardiomyopathy	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 46 of the MYL3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYL3-related disorders in the literature. This variant has been identified in 2/282580 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804879	SCV002050784	uncertain significance	not specified	2021-12-06	criteria provided, single submitter	clinical testing	Variant summary: MYL3 c.136T>C (p.Phe46Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251294 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.136T>C in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with other pathogenic variant has been reported (MYH7 c.1447G>A, p.E483K), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance.. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002381518	SCV002696114	uncertain significance	Cardiovascular phenotype	2019-09-29	criteria provided, single submitter	clinical testing	The p.F46L variant (also known as c.136T>C), located in coding exon 2 of the MYL3 gene, results from a T to C substitution at nucleotide position 136. The phenylalanine at codon 46 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001056549	SCV004843368	uncertain significance	Hypertrophic cardiomyopathy	2024-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 46 of the MYL3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/282580 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.