ClinVar Miner

Submissions for variant NM_000258.2(MYL3):c.170C>G (p.Ala57Gly) (rs139794067)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000722117 SCV000199362 uncertain significance not specified 2018-10-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala57Gly variant in MYL3 has been identified in at least 14 individuals with HCM (Lee 200 1, Choi 2010, Murakami 2014, GeneDx pers. comm., Ambry pers. comm., Invitae pers . comm., LMM data) and segregated with disease in 5 affected family members from 2 families (Lee 2001, Choi 2010). It has also been identified in 0.03% (5/17248 ) of East Asian chromosomes and 0.01% (12/111700) of European chromosomes by the Genome Aggregation Database (gnomAD,, which i s higher than the maximum expected allele frequency for a pathogenic variant in the MYL3 gene associated with autosomal dominant HCM. In vivo and in vitro funct ional studies provide some evidence that this variant impacts protein function; however, these types of assays may not accurately represent biological function (Muthu 2011, Lossie 2012, Kazmierczak 2013, Ma 2018). Computational prediction t ools and conservation analysis do not provide strong support for or against an i mpact to the protein. In summary, while there is some suspicion for a pathogenic role, based on the high allele frequency of this variant in the gnomAD populati on database the clinical significance of the p.Ala57Gly variant is uncertain. AC MG/AMP Criteria applied: PS3_Moderate; PP1_Moderate.
GeneDx RCV000024471 SCV000208873 pathogenic not provided 2018-10-23 criteria provided, single submitter clinical testing The A57G pathogenic variant in the MYL3 gene has been reported in multiple unrelated individuals diagnosed with HCM, all of Asian ancestry, and was absent from at least 900 control alleles (Lee et al., 2001; Choi et al., 2010; Murakami et al., 2014). Additionally, A57G is reported to segregate with HCM in five relatives from two different families (Lee et al., 2001; Choi et al., 2010). In a long-term follow-up study of carriers in one of these families, most affected relatives developed asymmetric septal hypertrophy, although there were variable symptoms and features of HCM reported (Choi et al., 2010). This variant has been observed in multiple other individuals referred for cardiomyopathy genetic testing at GeneDx. Furthermore, A57G was not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).While A57G is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across mammals. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. In vitro studies demonstrated that A57G decreases the binding affinity to the cardiac myosin heavy chain (Lossie et al., 2012), and functional studies in mouse models have shown that A57G disrupts myofilament function leading to hypertrophy (Kazmierczak et al., 2014). Finally, a likely pathogenic missense variant in the same residue (A57D) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), further supporting the functional importance of this residue.
Invitae RCV000229595 SCV000284301 uncertain significance Hypertrophic cardiomyopathy 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 57 of the MYL3 protein (p.Ala57Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs139794067, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed to segregate in a family with late-onset hypertrophic cardiomyopathy (HCM) (PMID: 11174330, 20641121) and has been observed in individuals with HCM (PMID: 27532257, 28193612, 29121657). ClinVar contains an entry for this variant (Variation ID: 31780). Experimental studies have shown that this missense change lowers the binding capacity of the MYL3 protein product to the myosin lever arm, compared to wild-type in vitro (PMID: 22131351). In addition, a study with transgenic mice demonstrated high levels of heart fibrosis and hypertrophy in mice expressing this missense change compared to wild-type (PMID: 23748425). 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.
Ambry Genetics RCV000243485 SCV000320097 pathogenic Cardiovascular phenotype 2017-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Center for Human Genetics,University of Leuven RCV000229595 SCV000579523 pathogenic Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score pathogenic
Integrated Genetics/Laboratory Corporation of America RCV000722117 SCV000696361 uncertain significance not specified 2018-09-06 criteria provided, single submitter clinical testing Variant summary: MYL3 c.170C>G (p.Ala57Gly) results in a non-conservative amino acid change located in the EF-hand domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3). The variant allele was found at a frequency of 7.3e-05 in 247150 control chromosomes (gnomAD). The observed variant frequency is approximately 2.9-fold above the estimated maximal expected allele frequency for a pathogenic variant in MYL3 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05), suggesting the variant is benign (ACMG BS1; however, not engaged since caution must be exercised when interpreting gnomAD control data with regard to cardiac phenotypes because it includes several large, well-phenotyped cardiac cohorts (e.g., Jackson Heart Study, Myocardial Infarction Genetics Consortium, etc.) and no phenotypic information about the individuals who had this variant is provided in this database). c.170C>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy. It was found in two unrelated Korean families with HCM (Lee_2001, Choi_2010) and two apparently unrelated Japanese HCM patients (Lee_2001, Murakami_2014) and was not found in 450 healthy controls. The two Korean families and one of the Japanese patients presented with a classic asymmetric septal hypertrophy and this variant was found to cosegregate with disease in both Korean families, with one family having five affected family members carrying the variant over two generations, though one unaffected family member carried the variant (age 48 at the time of Choi_2010 publication). Neither report on the Japanese patients included segregation data, thus these are not considered informative functional meioses (ACMG PP1-moderate). Overall, these data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. Although several studies report statistically significant differences in structure (e.g., fibrosis and myofilament disarray in a transgenic mouse [Muthu_2011]) and function (e.g., increased Ca2+ sensitivity and decreased maximal tension [Kazmierczak_2013]), the differences between the variant and controls in most of the data are relatively small and the biological significance is unknown (ACMG PS3; not engaged). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as pathogenic (ACMG PP5; however, not engaged due to discordance and ongoing classification debate among clinical laboratories). Based on the evidence outlined above, and considering the ACMG interpretation guidelines, the variant was classified as VUS-possibly pathogenic. This variant was re-classified following a discrepancy resolution discussion initiated by Dr. Birgit Funke and Megan Crawley to all ClinVar submitter labs in June-2018. A consensus of a VUS was agreed upon by all parties in the distribution.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709747 SCV000840024 pathogenic Familial hypertrophic cardiomyopathy 8 2017-04-10 criteria provided, single submitter clinical testing This c.170C>G (p.Ala57Gly) variant has previously been detected in several patients and families with hypertrophic cardiomyopathy [PMID 11174330, 20641121]. The penetrance of the disorder was estimated between 63 and 78% in carriers over 18 years of age [PMID 11174330, 20641121]. In vitro assays showed that the mutant protein has reduced binding affinity to myosin [PMID 22131351]. Transgenic mice expressing the mutant allele showed hypertrophic cardiomyopathy, consistent with the human phenotype [PMID 23748425]. This variant has been reported in 11 heterozygous individuals from the ExAC database ( This variant is conserved in mammals. Computer based prediction algorithms (SIFT and Polyphen-2) yield discordant results regarding the pathogenicity of this change. Nevertheless, based on reported patients and functional data, this variant is classified as pathogenic. Pathogenic variants in the MYL3 gene are considered medically actionable [ACMG59, PMID 27854360].
Leiden Muscular Dystrophy (MYL3) RCV000024471 SCV000045774 not provided not provided 2012-03-18 no assertion provided curation

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