ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.12254G>T (p.Arg4085Met) (rs375314465)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000442292 SCV000533649 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing The R4085M variant of uncertain significance in the ALMS1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been reported in several other individuals referred for cardiomyopathy genetic testing at GeneDx, although these individuals harbored additional cardiogenetic variants and no second variant in the ALMS1 gene was reported. The R4085M variant is observed in 8/24020 (0.03%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The R4085M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Counsyl RCV000670211 SCV000795041 uncertain significance Alstrom syndrome 2017-10-27 criteria provided, single submitter clinical testing
Invitae RCV000670211 SCV001236497 uncertain significance Alstrom syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with methionine at codon 4085 of the ALMS1 protein (p.Arg4085Met). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and methionine. This variant is present in population databases (rs375314465, ExAC 0.02%). This variant has not been reported in the literature in individuals with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 390736). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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