ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.3692G>A (p.Gly1231Glu) (rs372619046)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462849 SCV000541341 uncertain significance Alstrom syndrome 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 1231 of the ALMS1 protein (p.Gly1231Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs372619046, ExAC 0.05%). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 403935). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
GeneDx RCV000523577 SCV000618228 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The G1231E variant has not been published as pathogenic or reported as benign to our knowledge. This variant is observed in 10/23918 (0.04%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The G1231E 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, this substitution occurs at a position that is not conserved across species and glutamic acid (E) is the wild-type residue at this position in at least two mammalian species. Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to 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 are predicted to cause premature protein truncation (Marshall et al., 2012; Stenson et al., 2014).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.