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

dbSNP: rs139794067

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 In addition, a different change at the same pos ition, Ala57Gly, has been associated with HCM (Lee 2001, LMM unpublished data).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	2023-05-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies using human induced pluripotent stem cell (iPSC) lines demonstrated that p.(A57D) expressed in the heterozygous and homozygous state did not produce an HCM phenotype (PMID: 29914921); This variant is associated with the following publications: (PMID: 29687901, 24111713, 27483260, 21239446, 27574918, 28971120, 28518168, 29914921, 30624779, 31006259, 23426552, 31019283, 33288880, 34636345, 34509299, 34137518, 33935716, 29710196, 26779504, 29343803, 35653365)
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 Center for Human Genetics Tuebingen	RCV000158937	SCV000575351	likely pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV000538349	SCV000623765	uncertain significance	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 57 of the MYL3 protein (p.Ala57Asp). This variant is present in population databases (rs139794067, gnomAD 0.06%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21239446, 23426552, 24111713, 27483260). ClinVar contains an entry for this variant (Variation ID: 43121). 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 disruptive. Experimental studies have shown that this missense change does not substantially affect MYL3 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	2021-05-24	criteria provided, single submitter	clinical testing	The p.A57D variant (also known as c.170C>A), located in coding exon 3 of the MYL3 gene, results from a C to A substitution at nucleotide position 170. The alanine at codon 57 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been detected in individuals from hypertrophic cardiomyopathy (HCM) cohorts (Fokstuen S et al. J Med Genet. 2011;48:572-6; Almaas VM et al. Europace. 2013;15:1319-27; Berge KE et al. Clin Genet. 2014;86:355-60; Rubattu S et al. Int J Mol Sci, 2016 Jul;17:1239). This variant has also been identified in two unrelated homozygous individuals with HCM, both of whom had consanguineous parents and family histories of sudden death; heterozygous family members were reportedly unaffected, and one proband had three homozygous young children who had normal echocardiograms at the time of evaluation (Jaafar N et al. Genet Test Mol Biomarkers. 2016;20:674-679; Osborn DPS et al. Genet Med, 2021 Apr;23:787-792). In addition, multiple probands with this variant have had additional pathogenic variants in other HCM-associated genes (Ambry internal data; Broendberg AK et al. Eur J Hum Genet, 2018 03;26:303-313). Furthermore, this variant did not demonstrate a deleterious impact in several functional assays performed in human induced pluripotent stem cells heterozygous or homozygous for this alteration, although zebrafish models showed only partial rescue; given that the molecular mechanisms underlying HCM are not fully understood, the physiological significance of these results is unclear (Ma N et al. Circulation. 2018;138:2666-2681; Osborn DPS et al. Genet Med, 2021 Apr;23:787-792). 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). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755682	SCV000883095	uncertain significance	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	2019-12-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000238674	SCV000903653	uncertain significance	Cardiomyopathy	2023-12-17	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 57 of the MYL3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study with human-induced pluripotent stem cells has shown that this variant has no significant impact on MYL3 protein as determined by gene expression, sarcomere structure, cell size, contractility, action potentials and calcium handling (PMID: 29914921). However, another study with zebrafish knockdown model has shown that this variant is unable to rescue the compromised cardiac function as wild-type MYL3 does (PMID: 33288880). This variant has been reported in heterozygous multiple individuals affected with hypertrophic cardiomyopathy (PMID: 21239446, 23426552, 24111713, 27483260, 27574918, 33288880, 34137518, 37431535), as well as in five unrelated homozygous individuals (PMID: 27574918, 33288880, 34137518, 37431535). This variant has also been identified in 46/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant with uncertain functional impact that has been observed in the control population as well as in affected individuals. 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.
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 Laboratory Services, Illumina	RCV000755682	SCV001309352	uncertain significance	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.
Genetics and Genomics Program, Sidra Medicine	RCV000538349	SCV001434098	uncertain significance	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000755682	SCV003920887	likely pathogenic	Hypertrophic cardiomyopathy 8	2021-03-30	criteria provided, single submitter	clinical testing	MYL3 NM_000258.2 exon 3 p.Ala57Asp (c.170C>A): This variant has been reported in the literature in several individuals with HCM (Fokstuen 2011 PMID:21239446, Almaas 2013 PMID:23426552, Berge 2014 PMID:24111713, Jaafar 2015 PMID:26779504, Rubatta 2016 PMID:27483260, Dejgaard 2017 PMID:28971120). This variant is present in 0.05% (17/30616) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-46902303-G-T) and is present in ClinVar (Variation ID:43121). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, autosomal recessive inheritance carrier status, and/or variable expressivity. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, another variant at the same amino acid (p.Ala57Gly) has been reported in association with disease. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Dept of Medical Biology, Uskudar University	RCV003318341	SCV004022042	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PP2, PP3, BS3
Mayo Clinic Laboratories, Mayo Clinic	RCV000158937	SCV004226099	uncertain significance	not provided	2022-03-10	criteria provided, single submitter	clinical testing	BS1, PP3
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.