Submissions for variant NM_033118.4(MYLK2):c.260C>T (p.Ala87Val)

gnomAD frequency: 0.00014  dbSNP: rs121908107

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539484	SCV000652381	uncertain significance	Hypertrophic cardiomyopathy 1	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 87 of the MYLK2 protein (p.Ala87Val). This variant is present in population databases (rs121908107, gnomAD 0.05%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11733062). ClinVar contains an entry for this variant (Variation ID: 4243). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYLK2 protein function with a negative predictive value of 80%. 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.
GeneDx	RCV001588797	SCV001825851	likely benign	not provided	2020-09-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28082330, 30609406, 28518168, 26187847, 22995991, 11733062, 23299917)
Breda Genetics srl	RCV000539484	SCV001949903	uncertain significance	Hypertrophic cardiomyopathy 1	2020-10-30	criteria provided, single submitter	clinical testing	Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. The lack of one or more of the following features has discouraged further investigations: lack of a possible second hit in autosomal recessive conditions, presence of healthy controls in databases for autosomal dominant conditions, presence of unmatching cardinal clinical features in the patient or in the known gene-disease association, lack of segregation in the family, and/or variant type outside the known gene mutational spectrum.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155014	SCV003844403	likely benign	not specified	2025-02-18	criteria provided, single submitter	clinical testing	Variant summary: MYLK2 c.260C>T (p.Ala87Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 246866 control chromosomes, predominantly at a frequency of 0.00044 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK2 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05).c.260C>T has been reported in the literature in two individuals from the same family, who were affected with Hypertrophic Cardiomyopathy (Davies_2001), and in a later study in an individual with sudden unexplained death (Martinez-Matilla_2019). However, these reports do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. One of these publications reported experimental evidence evaluating an impact on protein function, and demonstrated increased V(max), however the variant protein tested in this study also carried another missense variant(s) in cis, therefore no conclusion can be made for the variant effect in isolation (Davies_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11733062, 34426522, 31376648). ClinVar contains an entry for this variant (Variation ID: 4243). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM	RCV000004465	SCV000024638	pathogenic	Cardiomyopathy, hypertrophic, midventricular, digenic	2001-11-30	no assertion criteria provided	literature only