ClinVar Miner

Submissions for variant NM_000258.2(MYL3):c.170C>A (p.Ala57Asp) (rs139794067)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618276 SCV000740087 likely pathogenic Cardiovascular phenotype 2017-12-18 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,Well-characterized mutation at same position
Blueprint Genetics RCV000157371 SCV000207109 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-07-07 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000238674 SCV000901610 uncertain significance Cardiomyopathy 2015-11-25 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000158937 SCV000575351 likely pathogenic not provided 2016-10-31 criteria provided, single submitter clinical testing
Color RCV000238674 SCV000903653 uncertain significance Cardiomyopathy 2018-06-05 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the EF hand domain of the MYL3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 21239446, 23426552, 24111713, 27483260, 27574918), including one homozygote with a family history of sudden cardiac death (PMID: 27574918). However, this variant has also been identified in 44/277138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at this codon (p.Ala57Gly) is classified as Pathogenic, suggesting that the alanine at this codon is important for MYL3 function and other missense variants at this position may also be deleterious. Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238674 SCV000296900 uncertain significance Cardiomyopathy 2015-11-30 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000755682 SCV000883095 uncertain significance Familial hypertrophic cardiomyopathy 8 2018-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000158937 SCV000208872 uncertain significance not provided 2018-12-18 criteria provided, single submitter clinical testing The A57D variant of uncertain significance in the MYL3 gene has been published in association with HCM (Fokstuen et al., 2011; Almaas et al., 2013; Berge et al., 2014; Jaafar et al., 2015; Rubattu et al., 2016; Dejgaard et al., 2017). At least two individuals harbored co-occurring cardiogenetic variants (Berge et al., 2014; Rubattu et al., 2016). The A57D variant has also been identified, both independently of and in conjunction with additional cardiogenetic variants, in multiple unrelated individuals referred for HCM genetic testing at GeneDx. No informative segregation data are available. The A57D variant is observed in 17/30,782 (0.06%) alleles from individuals of South Asian ancestry and 44/277,138 (0.016%) global alleles in large population cohorts (Lek et al., 2016).The A57D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, a different missense variant affecting the same residue (A57G) 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. However, functional studies using human induced pluripotent stem cell (iPSC) lines demonstrated that A57G expressed in the homozygous state did not produce an HCM phenotype (Ma et al., 2018).
Invitae RCV000538349 SCV000623765 uncertain significance Hypertrophic cardiomyopathy 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 57 of the MYL3 protein (p.Ala57Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs139794067, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with hypertrophic cardiomyopathy, including an observation in a homozygous individual (PMID: 24111713, 21239446, 27483260, 23426552, 28971120). ClinVar contains an entry for this variant (Variation ID: 43121). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Ala57Gly) has been determined to be pathogenic (PMID: 11174330, 20641121, 11174330, 22131351, 23748425). This suggests that the alanine residue is critical for MYL3 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036019 SCV000059671 uncertain significance not specified 2013-08-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Ala57Asp va riant in MYL3 has not been reported in the literature, but has now been identifi ed by our laboratory in two individuals with HCM. One of these individuals carri ed a pathogenic variant in another gene, while the other individual was homozygo us for the variant. Of note, the homozygous individual had an affected cousin wh o was also homozygous for the variant. Consanguinity was reported in the family and both sets of parents were reportedly unaffected. While this may indicate tha t the variant is disease causing in the recessive state, there is no support for recessive inheritance of MYL3 variants. This variant has also been identified i n 1/4406 African American chromosomes by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS/). In addition, a different change at the same pos ition, Ala57Gly, has been associated with HCM (Lee 2001, LMM unpublished data). Computational analyses (biochemical amino acid properties, conservation, AlignGV GD, PolyPhen2, and SIFT) suggest that the Ala57Asp variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, although this data supports that the Ala57Asp variant may be pathoge nic, additional studies are needed to fully assess its clinical significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158937 SCV000924884 uncertain significance not provided 2016-06-29 no assertion criteria provided provider interpretation MYL3 p.Ala57Asp (c.170C>A) (NM_000258.1) There is moderate case data with some segregation demonstrated, but the variant is also seen at relatively high frequency in population databases and has been seen in combination with a pathogenic variant and in a homozygous state in an unaffected individual. We consider this conflicting data and deem the variant to be a variant of uncertain significance. We do not feel that this variant is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in an individual with HCM. Testing was performed by Familion. The variant has been seen in at least 5 unrelated cases of HCM (not including this patient's family). There is conflicting case data. This variant has been reported in 1 individual with HCM by Fokstuen et al., 2011, and in 1 individual with HCM by Almaas et al., 2013. It has also been reported in a Korean family, segregating with disease in 5 individuals with HCM by Choi et al., 2010. Controls/Population data: The variant has not been seen in 400 Familion laboratory controls. The variant was reported online in 14 of 60,669 (0.023%) individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/25/16). Specifically, the variant was observed in following ethnicities European (Non-Finnish) 5/33,342; East Asian 3/4,323; Latino 1/5,787; South Asian 5/8,256. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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