ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.8125A>C (p.Met2709Leu) (rs371904071)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000428610 SCV000532219 uncertain significance not provided 2016-10-03 criteria provided, single submitter clinical testing 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).
Invitae RCV000457298 SCV000541343 uncertain significance Alstrom syndrome 2016-12-24 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 2709 of the ALMS1 protein (p.Met2709Leu). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs371904071, ExAC 0.001%) but has not been reported in the literature in individuals with an ALMS1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000457298 SCV000792969 uncertain significance Alstrom syndrome 2017-07-25 criteria provided, single submitter clinical testing

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