ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.2539G>A (p.Gly847Arg) (rs201154998)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767099 SCV000535129 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ALMS1 gene. The G847R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and no homozygous individuals have been reported. In addition, the G847R 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, and arginine (R) is tolerated in at least two species. Finally, in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000468401 SCV000541359 uncertain significance Alstrom syndrome 2019-05-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 847 of the ALMS1 protein (p.Gly847Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs201154998, ExAC 0.1%). This variant has not been reported in the literature in individuals with ALMS1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The arginine 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 RCV000418320 SCV000864111 uncertain significance not specified 2017-01-03 criteria provided, single submitter clinical testing Variant summary: The ALMS1 c.2533G>A (p.Gly845Arg, alternative name c.2539G>A) variant involves the alteration of a non-conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 11/120594 control chromosomes at a frequency of 0.0000912, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALMS1 variant (0.0022361). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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