ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.3103C>T (p.Pro1035Ser) (rs531648685)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431219 SCV000532159 uncertain significance not provided 2017-05-17 criteria provided, single submitter clinical testing The P1036S 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. The P1036S 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 serine is the wild-type amino acid at this position in at least two species. In silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, the P1036S variant has been observed in 3/11,550 alleles from individuals of Latino ancestry and 5/66,684 alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016).
Invitae RCV001242965 SCV001416091 uncertain significance Alstrom syndrome 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1036 of the ALMS1 protein (p.Pro1036Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs531648685, ExAC 0.03%). This variant has not been reported in the literature in individuals with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 389575). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001251290 SCV001426826 uncertain significance not specified 2021-04-26 criteria provided, single submitter clinical testing Variant summary: ALMS1 c.3100C>T (p.Pro1034Ser) results in a non-conservative amino acid change located in the Alstrom syndrome repeat (IPR040972) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 248852 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (8e-05 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3100C>T in individuals affected with Alstrom Syndrome With Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with other pathogenic variant has been reported internally (LMNA c.949G>A, p.Glu317Lys), providing supporting evidence for a benign role. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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