ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.10895G>A (p.Arg3632His) (rs142558799)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766969 SCV000533001 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The R3632H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 78/276814 (0.003%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The R3632H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nonetheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000431898 SCV000713800 uncertain significance not specified 2017-12-21 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg3632His va riant in ALMS1 gene has not been previously reported in individuals with hearing loss or Alstrom syndrome, but has been identified in several populations by the Genome Aggregation Database with the highest frequency of 0.21%(51/24014) of Af rican chromosomes (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142558799). This variant has also been reported in an affected individual of unspecified ph enotypes in ClinVar (Variation ID: 390222). Computational prediction tools and c onservation analysis do not provide strong support for or against an impact to t he protein. In summary, while the clinical significance of the p.Arg3630His vari ant is uncertain, the frequency data indicate that it is more likely to be benig n. ACMG/AMP criteria applied: BS1_supporting.
Invitae RCV000634800 SCV000756144 uncertain significance Alstrom syndrome 2018-02-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 3632 of the ALMS1 protein (p.Arg3632His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs142558799, ExAC 0.2%). This variant has not been reported in the literature in individuals with ALMS1-related disease. ClinVar contains an entry for this variant (Variation ID: 390222). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: 0; Align-GVGD: Class C25. The Histidine 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 and their clinical significance is uncertain. 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.
Integrated Genetics/Laboratory Corporation of America RCV000431898 SCV000864101 uncertain significance not specified 2018-05-29 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.10889G>A (p.Arg3630His, alternative name c.10895G>A) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 276814 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.00028 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.10889G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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