This rare variant is reported to cause late-onset familial hypertrophic cardiomyopathy. The variant has been found in five affected Caucasian individuals (in four families), but affected non-carriers and unaffected carriers have also been observed. No statistically significant enrichment of this variant in cases vs. controls has been shown. This variant is reported in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/14064/) with conflicting interpretations: two sources classify it as pathogenic, three as “uncertain significance”, and one as “likely benign”.

High clinical importance, Uncertain pathogenic

dominant

The A13T variant has been reported in the literature (Poetter 1996, Szczesna 2001, Andersen 2001, Szczesna-Cordary 2004, Hougs 2005) but there is conflicting evidence regarding its pathogenicity. The variant was identified in two HCM probands as well as two affected family members and the variant was absent from at least 678 control chromosomes tested across both studies (Poetter 1996, Andersen 2001, Hougs 2005). However, this variant was not detected in one affected individual in the Anderson/Hougs family, raising some question as to whether it is the causative variant in the family. Later the authors identified a second variant, N1327K in MYH7, and proposed that this family had two mutations segregating. However, we have since accumulated enough data to suggest that N1327K is not disease-causing. While there is a possibility that the non-segregating family member has disease due to an environmental etiology (obesity and hypertension were noted), there is also the possibility that a third variant is actually responsible for disease (Hougs 2005). Functional studies examining effects of this mutation on protein function were not conclusive (Szczesna 2001, Szczesna-Cordary 2004).

Harvard LMM has also identified the A13T variant in another family; however, the variant only segregated with disease in 2/3 individuals. This data cannot be used in case/control statistics as the total number of individuals with hypertrophic cardiomyopathy screened by LMM for mutations in this gene is unavailable.

This variant is seen in a PGP participant (hu04FD18) who is healthy, had a normal cardiac evaluation, and no family history of heart disease. It should also be noted that most, if not all, of the individuals with the A13T variant are of Ashkenazi Jewish ancestry, and a screen of 116 healthly Ashkenazi Jewish controls was negative for the variant. In summary, the lack of segregation of the variant with disease in two affected individuals in the two families studied suggests that the variant may not be disease-causing; however, a conclusion cannot be made with certainty at this point.

HCM is not 100% penetrance, so a single healthy observation is insufficient to prove this variant is not pathogenic. However, observations reported to date lack statistical significance. Observations of PGP + public genomes used by GET-Evidence are combined with Ashkenazi Jewish controls for the control numbers used in the unpublished case/controls.

See also: http://genepath.med.harvard.edu/seidman//cg3/muts/MYL2_Ala13Thr.html