ClinVar

Description

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 (http://exac.broadinstitute.org/), 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).