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

dbSNP: rs794727174

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175088	SCV000226516	uncertain significance	not provided	2014-07-18	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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, http://gnomad.broadinstitute.org; 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	Familial aplasia of the vermis	2022-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 761 of the AHI1 protein (p.Ser761Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Joubert syndrome (PMID: 25616960). ClinVar contains an entry for this variant (Variation ID: 194664). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AHI1 protein function. 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.
GeneDx	RCV000175088	SCV002577138	uncertain significance	not provided	2022-09-28	criteria provided, single submitter	clinical testing	Observed in homozygous state in siblings with retinitis pigmentosa, however, these siblings were homozygous for an additional variant in AHI1 which may have also contributed to the clinical features (Elsayed et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25616960, 16453322, 28442542)
OMIM	RCV000185588	SCV000238482	pathogenic	Joubert syndrome 3	2015-05-01	no assertion criteria provided	literature only