ClinVar Miner

Submissions for variant NM_001134831.2(AHI1):c.1033T>A (p.Leu345Met) (rs200927282)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724880 SCV000232753 uncertain significance not provided 2015-06-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000250813 SCV000312857 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001155546 SCV001316982 uncertain significance Joubert syndrome 3 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae RCV001206260 SCV001377558 uncertain significance Joubert syndrome 2019-10-01 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 345 of the AHI1 protein (p.Leu345Met). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs200927282, ExAC 0.03%). This variant has not been reported in the literature in individuals with AHI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 198882). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The methionine 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.

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