ClinVar Miner

Submissions for variant NM_000258.3(MYL3):c.170C>G (p.Ala57Gly) (rs139794067)

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Total submissions: 9
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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 2021-03-02 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 15 individuals with HCM (Lee 2001 PMID: 11174330, Choi 2010 PMID: 20641121, Murakami 2014 (no PMID), Robyns 2020 PMID: 31513939, 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 PMID: 11174330, Choi 2010 PMID: 20641121). It has also been reported by other clinical laboratories in ClinVar (Variation ID 31780) and has been identified in 0.03% (5/18394) of East Asian chromosomes and 0.01% (12/113750) of European chromosomes by the Genome Aggregation Database (gnomAD,, which is 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 functional studies provide some evidence that this variant impacts protein function; however, these types of assays may not accurately represent biological function (Muthu 2011 PMID: 21885653, Lossie 2012 PMID: 22131351, Kazmierczak 2013 PMID: 23748425, Ma 2018 PMID: 29914921). Computational prediction tools and conservation analysis do not provide strong support for or against an impact 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 population database the clinical significance of the p.Ala57Gly variant is uncertain. ACMG/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 2020-07-07 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 uncertain significance Cardiovascular phenotype 2019-09-12 criteria provided, single submitter clinical testing The p.A57G variant (also known as c.170C>G), located in coding exon 3 of the MYL3 gene, results from a C to G substitution at nucleotide position 170. The alanine at codon 57 is replaced by glycine, an amino acid with similar properties. This mutation has been detected in multiple unrelated patients with hypertrophic cardiomyopathy and was reported to co-segregate with disease in two unrelated families (Lee W et al., Am. Heart J. 2001 Feb; 141(2):184-9; Choi JO et al., Clin Cardiol 2010 Jul; 33(7):430-8; Murakami C et al., Kitasato Med J 2014; 44:47-55; Weissler-Snir A et al. Circ Cardiovasc Imaging, 2017 Feb;10:; Ambry internal data; LMM pers. comm.). However, this alteration has also been identified in unaffected individuals and as a secondary finding in individuals who underwent whole exome sequencing for non-cardiovascular indications (Jang MA et al. Genet. Med., 2015 Dec;17:1007-11; Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-817; Natarajan P et al. Sci Transl Med, 2016 11;8:364ra151; Ambry internal data). Moreover, this alteration is present in population databases with an allele count greater than expected for a pathogenic variant (Whiffin N et al. Genet. Med. 2017;19:1151-1158). Based on data from gnomAD, the G allele has an overall frequency of approximately 0.007% (18/251470) total alleles studied. The highest observed frequency was 0.03% (5/18394) of East Asian alleles. Multiple functional studies suggest that this alteration may impact MYL3 structure and function, but the observed differences are relatively minor and the clinical relevance is uncertain (Muthu P et al., FASEB J. 2011 Dec; 25(12):4394-405; Lossie J et al., Cardiovasc. Res. 2012 Mar; 93(3):390-6; Kazmierczak K et al., Am. J. Physiol. Heart Circ. Physiol. 2013 Aug; 305(4):H575-89; Ma N et al. Circulation, 2018 Dec;138:2666-2681; Wang Y et al. Open Biol, 2018 04;8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Center for Human Genetics,University of Leuven RCV000229595 SCV000579523 pathogenic Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score pathogenic
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000722117 SCV000696361 uncertain significance not specified 2020-09-04 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 (IPR002048) 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 7.1e-05 in 252370 control chromosomes (gnomAD). The observed variant frequency is approximately 2.9- fold the estimated maximal expected allele frequency for a pathogenic variant in MYL3 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05), suggesting that the variant is benign. This data should be interpreted with caution in regard to cardiac phenotypes, however, as gnomAD control data includes several 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 are provided in this database (ACMG BS1, not engaged). c.170C>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy. Most notably, it was found in two unrelated Korean families with HCM in which affected individuals presented with a classic asymmetric septal hypertrophy (Lee_2001, Choi_2010). The variant was shown to cosegregate with disease in both of these families, with one family having five affected family members carrying the variant over two generations, although the variant appeared to demonstrate incomplete penetrance as one unaffected family member carried the variant (age 48 at the time of Choi_2010 publication). The variant has also been reported in other HCM patients, although with limited evidence (such as cosegregation data) for causality (examples- Lee_2001, Murakami_2001, Weissler-Snir_2017, Ho_2018, Robyns_2020, Chung_2020, Kim_2020). Overall, these data indicate that the variant may be associated with disease (ACMG PP1 moderate). However, the variant has also been reported in at least one additional unaffected individual (Natarajan_2016). 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). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (uncertain significance, n=4; pathogenic, n=3). 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. As of Dec-2018, this variant was slated for finalization as a consensus VUS by the ClinGen expert review panel (personal correspondence, Dr. Funke, Melissa A. Kelly). Based on the evidence outlined above, the variant was re-evaluated to retain its previous classification as VUS-possibly pathogenic.
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].
Color Health, Inc RCV001184759 SCV001350820 uncertain significance Cardiomyopathy 2020-03-26 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (MYL3) RCV000024471 SCV000045774 not provided not provided 2012-03-18 no assertion provided curation

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