Submissions for variant NM_000258.3(MYL3):c.170C>A (p.Ala57Asp) (rs139794067)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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 In addition, a different change at the same pos ition, Ala57Gly, has been associated with HCM (Lee 2001, LMM unpublished data).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.
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).
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000238674	SCV000296900	uncertain significance	Cardiomyopathy	2015-11-30	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000158937	SCV000575351	likely pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV000538349	SCV000623765	uncertain significance	Hypertrophic cardiomyopathy	2019-12-13	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). This variant has been reported not to substantially affect MYL3 protein function (PMID: 29914921). 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	RCV000618276	SCV000740087	uncertain significance	Cardiovascular phenotype	2019-01-23	criteria provided, single submitter	clinical testing	Insufficient evidence
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
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000238674	SCV000901610	uncertain significance	Cardiomyopathy	2015-11-25	criteria provided, single submitter	clinical testing
Color	RCV000238674	SCV000903653	uncertain significance	Cardiomyopathy	2020-03-17	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute	RCV000538349	SCV001156273	likely benign	Hypertrophic cardiomyopathy	2018-06-19	criteria provided, single submitter	research	The MYL3 Ala57Asp has been previously identified in HCM cases (Jaafar N, et al., 2016; Almaas VM, et al., 2013; Vazquez-Alvarez MC, et al., 2012; Fokstuen S et al., 2011; Calore C, et al., 2011; Choi JO, et al., 2010). The cases reported by Vazquez-Alvarez MC, et al. (2012) included a prenatal HCM case, however the patient was also diagnosed with Noonan syndrome. An iPSC-CM model showed that both heterozygous and homozygous cardiac cells did not produce an HCM phenotype (Ma N, et al., 2018). Interestingly a different change at this position (Ala57Gly) has been reported in multiple HCM cases, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, PolyPhen2 and MutationTaster predict this variant to have a deleterious effect. The variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/), at an allele frequency of 0.0001588, which is higher then expected for HCM. We identified this variant in an HCM patient with a family history of HCM. A second variant (ACTC1 Ala323Val) was also identified in this patient. The ACTC1 variant was found to segregate to an affected fourth degree relative but MYL3 Ala57Asp did not segregate. The variant has been found to segregate with disease in two homozygous siblings reported by LMM (ClinVar: SCV000208872). In summary, based on the lack of phenotype in iPSC-CM, high allele frequency and non-segregation in affected family members, we classify MYL3 Ala57Asp (in the heterozygous form) as "likely benign".
Illumina Clinical Services Laboratory,Illumina	RCV000755682	SCV001309352	uncertain significance	Familial hypertrophic cardiomyopathy 8	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Blueprint Genetics	RCV000157371	SCV000207109	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-07-07	no assertion criteria provided	clinical testing
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.