ClinVar Miner

Submissions for variant NM_000258.3(MYL3):c.427G>A (p.Glu143Lys) (rs104893750)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000199993 SCV000059674 likely pathogenic Hypertrophic cardiomyopathy 2019-08-22 criteria provided, single submitter clinical testing The p.Glu143Lys variant in MYL3 has been reported in the heterozygous state in >35 individuals with hypertrophic cardiomyopathy (HCM), many of whom are of reported Latino ancestry, suggesting it may be a founder mutation in that population (Gomez 2014, McNamara 2017, LMM data, GeneDx pers. comm., Invitae pers. comm., Ambry pers. comm.). A few of these individuals also carried a likely pathogenic variant in another HCM-associated gene. This variant has also been identified in the homozygous state in at least 5 individuals with early onset HCM or restrictive cardiomyopathy (RCM) and in 3 affected siblings who also had early onset disease (Olson 2002, Caleshu 2011, LMM data, Ambry pers. comm., Invitae pers comm.). Relatives who were heterozygous carriers of this variant were clinically unaffected (Olson, 2002, Caleshu 2011) suggesting reduced penetrance. Additionally, it has been reported by other clinical laboratories in ClinVar (Variant ID: 14063) and has been identified in 0.01% (4/35436) of Latino chromosomes by gnomAD ( In vitro and in vivo functional studies, including transgenic mice expressing the p.Glu413Lys human variant that had clinical features of RCM, support an impact on protein function (Lossie 2012, Sahni 2015, Yuan 2017). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for HCM with reduced penetrance and is associated a more severe presentation when a pathogenic variant is also found on the second copy of the gene. ACMG/AMP Criteria applied: PS4, PS3_Moderate, PP3.
GeneDx RCV000497294 SCV000208882 likely pathogenic not provided 2018-10-17 criteria provided, single submitter clinical testing The E143K likely pathogenic variant in the MYL3 gene has been published previously in association with HCM (Olson et al., 2002; McNamara et al., 2017; Walsh et al., 2017) and restrictive cardiomyopathy (RCM) (Caleshu et al., 2011). Olson et al. (2002) reported homozygous E143K in two children who had HCM with mid-cavitary left ventricular hypertrophy, severe biatrial enlargement, and restrictive physiology (Olson et al., 2002). Heterozygous family members, including the affected children's consanguineous parents, were unaffected, consistent with possible autosomal recessive inheritance (Olson et al., 2002). E143K was described in conjunction with a MYBPC3 gene variant in a 38 year-old female patient with HCM who underwent myectomy surgery to relieve left ventricular outflow tract obstruction (McNamara et al., 2017). Additionally, an individual of Central American ancestry with RCM was identified as homozygous for the E143K variant and heterozygous for another variant in the MYL2 gene; the individual's unaffected mother was heterozygous for both variants (Caleshu et al., 2011). E143K has been identified independently in the heterozygous state in multiple individuals (primarily of Latino ancestry) with HCM referred for genetic testing at GeneDx. This variant was not present in 102 control individuals of Central American origin (Caleshu et al., 2011), and is not observed at a significant frequency in large population cohorts (Lek et al., 2016).E143K 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. Moreover, in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A functional study conducted by Lossie et al. (2012) suggests that this variant may affect MYH binding affinity. Subsequently, McNamara et al. (2017) postulated that E143K, in combination with a MYBPC3 gene variant, adversely affects the super-relaxed state (SRX) of myosin, thus impairing cardiac contractility. However, additional studies are needed to validate the specific functional effect of the E143K variant.
Invitae RCV000199993 SCV000254448 pathogenic Hypertrophic cardiomyopathy 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 143 of the MYL3 protein (p.Glu143Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. While this variant is not present in the ExAC population database, it is present in the Latino subpopulation of the gnomAD population database (rs104893750, 0.0087%). This variant has been reported in the homozygous state in four individuals with restrictive cardiomyopathy from three families (PMID: 12021217, 21823217, Invitae). In addition, this variant has been observed in the heterozygous state in more than ten unrelated individuals with hypertrophic cardiomyopathy (PMID: 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 14063). Experimental studies have shown that this missense change leads to a reduced affinity for the cardiac myosin heavy chain in the sarcomere (PMID: 22131351). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000249729 SCV000319085 likely pathogenic Cardiovascular phenotype 2019-05-05 criteria provided, single submitter clinical testing Deficient protein function in appropriate functional assay(s);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000497294 SCV000885788 uncertain significance not provided 2017-06-08 criteria provided, single submitter clinical testing The p.Glu143Lys variant (rs104893750) has been previously identified in two families of Latin American ethnicity (Caleshu 2011 and Olson 2002), and in a large cohort of patients referred for testing due to cardiomyopathy (Walsh 2017). Pathogenic variants in MYHL3 are typically associated with dominantly inherited hypertrophic cardiomyopathy (HCM8; MIM: 608751). However, in the two families described in Caleshu et al (2011) and Olson et al (2002), affected individuals were homozygous for the p.Glu143Lys, whereas a total of five heterozygous carriers between both families (ages 7-70) were clinically unaffected. Consanguinity was confirmed in the family described in Olsen et al (2002), and the authors suggested the p.Glu143Lys variant acts in a recessive manner, likely through a mechanism distinct from other dominantly inherited pathogenic MYL3 variants. At least one functional study of several pathogenic variants in MYL3, including p.Glu143Lys, revealed similar defects compared to wild-type in the binding of variant MYL3 protein to myosin heavy chain. However, these functional observations are difficult to interpretation, as the exact molecular mechanisms underlying the physiological defects associated with MYL3 remain unknown. Furthermore, to our knowledge, no other recessive-acting pathogenic alleles have been identified in MYL3, and all clinical laboratories submitting to ClinVar also classify the p.Glu143Lys variant as being of uncertain clinical significance (Variation ID: 14063). The glutamic acid at codon 143 is highly conserved considering 14 species up to C. elegans (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on MYL3 protein structure/function (SIFT: damaging, PolyPhen2: possibly damaging, and Mutation Taster: disease causing). In summary, based on the available information, the clinical significance of the p.Glu143Lys variant cannot be determined with certainty.
Color RCV001186218 SCV001352584 uncertain significance Cardiomyopathy 2019-07-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001201266 SCV001372376 pathogenic Primary familial hypertrophic cardiomyopathy 2020-06-16 criteria provided, single submitter clinical testing Variant summary: MYL3 c.427G>A (p.Glu143Lys) results in a 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. The variant allele was found at a frequency of 1.2e-05 in 251486 control chromosomes (gnomAD). c.427G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (HCM) (e.g. Gomez_2017, Ho_2018, Mademont-Soler_2017, McNamara_2017, Miller_2019, Olson_2002, Walsh_2017). At least two studies report individuals affected with childhood-onset HCM or early-onset restrictive cardiomyopathy that were homozygous for the variant, while multiple heterozygote family members were reported as unaffected with no evidence of cardiomyopathy (Caleshu_2011, Olson_2002). Olson et al (2002) postulated that the variant causes recessive cardiomyopathy and acts through a different molecular mechanism of disease than other dominantly-inherited MYL3 pathogenic variants. Additional studies reported the variant in HCM individuals co-occurring with variants from other cardiomyopathy genes (e.g. MYBPC3 p.I539V, TTN p.T6325A and p.R24188T, MYBPC3 p.D770N) (Gomez_2017, Mademont-Soler_2017, McNamara_2017). At least one of these is a known pathogenic variant (MYBPC3 p.D770N) and through their studies on the super-relaxed state (SRX) of myosin, the authors suggested that the combination of the two variants may cause a compound heterozygous effect (McNamara_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (e.g. Lossie_2012, Sahni_2015). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic (n=4) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000015107 SCV000035364 pathogenic Familial hypertrophic cardiomyopathy 8 2011-09-01 no assertion criteria provided literature only
Leiden Muscular Dystrophy (MYL3) RCV000015107 SCV000045775 not provided Familial hypertrophic cardiomyopathy 8 2012-03-18 no assertion provided curation
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000036022 SCV000280389 uncertain significance not specified 2013-12-30 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Glu143Lys (c.427G>A) We last reviewed this variant in 2013. In August 2015 we updated the review with ClinVar and ExAC. We did not look for additional case data given that the available data is conflicting. Per ClinVar, GeneDx and LMM both classify it as a variant of uncertain significance. The variant has been seen in at least 8 maybe 9 cases of cardiomyopathy. At least 5 of these individuals are Hispanic. At least three have another pathogenic variant. Olsen and colleagues report this variant in a family in which three siblings presented with restrictive cardiomyopathy in the second decade of life with an apparent autosomal recessive mode of inheritance. There was known consanguinity (parents were second cousins). The phenotype includes mid-cavitary left ventricular hypertrophy with mild dynamic obstruction in systole. Systolic function was normal, but restrictive physiology was diagnosed on the basis of Doppler measurements, severe biatrial enlargement, and mild pulmonary hypertension. Two siblings were found to be homozygous for this variant (no sample was available for the third). A fourth sibling, parents (age 40) and paternal grandfather (age 70) were all found to be heterozygous and clinically unaffected. The ancestry of this patient was not reported. (Olsen T et al., 2002). This variant was also described in the homozygous state in a patient from El Salvador with restrictive cardiomyopathy and no signs of left ventricular hypertrophy. This individual also carried the p.Gly57Glu in MYL2 gene. The patient’s mother was the only family member available for evaluation. On genetic testing she was found to be a double heterozygote for the p.Glu143Lys mutation in MYL3 and the p.Gly57Glu mutation in MYL2. She had a normal transthoracic echocardiogram, electrocardiogram, and physical exam at 45 years of age (Caleshu et al., 2011) This variant is in coding exon 4 of 7 exons. MYL3 is a calcium binding protein and acts as a stabilizer of the myosin head. In a functional study of rat cardiomyopcytes, recombinant protein produced with this alteration was shown to significantly lower the binding affinity to the myosin heavy chain (Lossie J et al., 2012). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The Glutamic acid at codon 143 is conserved across species, as are neighboring amino acids. The variant was entered into dbSNP(build 36) as rs104893750 based on the report by Olson et al. but has not been found independently by any other SNP discovery efforts. SNP rs104893750 is absent from HapMap data release 28. There is no nonsynonymous variation at codon 143 listed in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of August 27th, 2015). Of note given the patient's ancestry and the case data, this includes 5789 Latino individuals. I checked coverage at that site and the mean and median coverage were over 90 (3-46901019-C-T).

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