ClinVar Miner

Submissions for variant NM_001134831.2(AHI1):c.2282C>T (p.Ser761Leu) (rs794727174)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD, LLC RCV000175088 SCV000226516 uncertain significance not provided 2014-07-18 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000185588 SCV000786692 uncertain significance Joubert syndrome 3 criteria provided, single submitter research Our study detected the homozygous p.Ser761Leu variant in one indidivual with Joubert syndrome. It has been previously reported in ClinVar with conflicting pathogenicities (Variant ID: 194664). This variant was initially reported in a heterzygous state in an unaffected parent but was not present in the proband with Joubert syndrome (Valente 2006). Later, two siblings with Joubert syndrome were both found to be homozygous for the p.Ser761Leu variant (Elsayed 2015). None of their unaffected siblings or parents were homozygous for the p.Ser761Leu variant. The two affected siblings were also homozygous for a second variant (Trp1088fs), however that variant is also of uncertain significance (VariantID ID: 2013).This variant has been identified in 1/32462 of Latino chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs794727174). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Additionally, this position is noted to be multiallelic in gnomAD (0.01%; dbSNP rs794727174). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser761Leu variant is uncertain.
Invitae RCV001053820 SCV001218101 uncertain significance Joubert syndrome 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 761 of the AHI1 protein (p.Ser761Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Joubert syndrome (PMID:25616960). ClinVar contains an entry for this variant (Variation ID: 194664). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
OMIM RCV000185588 SCV000238482 pathogenic Joubert syndrome 3 2015-05-01 no assertion criteria provided literature only

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