ClinVar

Description

A variant of uncertain significance has been identified in the ALMS1 gene. The M2709L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M2709L variant was not observed with any significant frequency in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, the M2709L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position not evolutionarily conserved and Leucine is the native amino acid at this position in multiple vertebrate species. In silico analysis predicts this variant likely does not alter the protein structure/function. Lastly, while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants in ALMS1 reported to date introduce a premature termination codon (Marshall et al., 2012; Stenson et al., 2014).