ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.12116A>G (p.Gln4039Arg) (rs1057524132)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000421465 SCV000534640 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing The c.12116 A>G (Q4039R) variant of uncertain significance in the ALMS1 gene has not been published as a pathogenicvariant, nor has it been reported as a benign variant to our knowledge. c.12116 A>G (Q4039R) was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, norwas it observed in the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in thesepopulations.At the nucleotide level, c.12116 A>G (Q4039R) affects the penultimate nucleotide in exon 19 of the ALMS1 gene. Thissubstitution occurs at a nucleotide position that is highly conserved, though guanine is the native nucleotide at this site inat least one species. In silico splicing algorithms were not informative regarding whether this variant is predicted to resultin an adverse splicing event. Nevertheless, in the absence of functional mRNA studies, the physiological consequence ofthis variant on splicing cannot be precisely determined.At the protein level, the c.12116 A>G (Q4039R) variant is a semi-conservative amino acid substitution, which may impactsecondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a position thatis conserved across species, and in silico analysis predicts this variant is probably damaging to the proteinstructure/function. However, no pathogenic missense variants in nearby residues have been reported in the Human GeneMutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causingvariants.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. No secondpathogenic variant was found in the ALMS1 gene, as would be expected for an autosomal recessive disorder. This resultcannot be interpreted for diagnosis or used for family member screening at this time.

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