ClinVar

Description

The Arg162Trp variant in TNNI3 has been reported in 1 Japanese individual with HCM and was absent from over 500 control chromosomes (Kimura 1997). It has also been identified in 1/8314 European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Cell culture studies showed that the variant compromises TNNI3 function (Elliott 2000, Takahashi-Yanaga 2001). Our laboratory has detected the variant in 4 individuals with HCM (1 Caucasian adult, 2 Indian adolescents, and 1 Jordanian adolescent). In two of the non-Caucasian families (one Indian and one Jordanian), the inheritance was consistent with a recessive mode (3 affected individuals were homozygous from the 2 families and none of the heterozygous individuals were affected). In contrast, the previously reported individual with HCM (Kimura 1997), the Caucasian individual and one Indian individual tested by our laboratory were heterozygous, which is consistent with dominant inheritance. Although recessive inheritance has been described for the TNNI3 gene (Ala2Val; Murphy 2004), it is also possible that the Arg162Trp variant is common in Middle Eastern and/or Asian populations and therefore less likely to be disease-causing. At this time, we cannot rule out this possibility because control studies are not available for these populations. Arginine (Arg) at position 162 is conserved in mammals except two bat species, but not in evolutionarily distant species, raising the possibility that a change at this position may be tolerated or have a weaker effect. However, two other likely disease-causing variants have been identified at this position (Arg162Pro, Arg162Gln). In summary, it is possible that this variant is disease-causing, but has a milder effect in isolation (heterozygous) and results in HCM when seen with another variant(s) (homozygous or compound heterozygous). However, additional studies are required to further assess its clinical significance.