Submissions for variant NM_003322.6(TULP1):c.1087G>A (p.Gly363Arg)

dbSNP: rs1761067394

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001346724	SCV001540949	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 363 of the TULP1 protein (p.Gly363Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with inherited retinal dystrophy (PMID: 26103963, 33921607; Invitae). ClinVar contains an entry for this variant (Variation ID: 1042725). 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 TULP1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376325	SCV001573432	uncertain significance	Retinitis pigmentosa 14	2021-04-08	criteria provided, single submitter	research	The TULP1 c.1087G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
GeneDx	RCV001346724	SCV003923657	uncertain significance	not provided	2022-11-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27440997, 31574917, 26103963, 33921607, 34865612)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699323	SCV005203505	pathogenic	Leber congenital amaurosis	2024-07-16	criteria provided, single submitter	clinical testing	Variant summary: TULP1 c.1087G>A (p.Gly363Arg) results in a non-conservative amino acid change located in the Tubby, C-terminal domain (IPR000007) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251412 control chromosomes. c.1087G>A has been reported in the literature in multiple homozygous individuals affected with inherited retinal dystrophy and/or cone and cone-rod dystrophy (example, Azab_2021, Boulanger-Scemama_2015), and segregated with disease in at least 1 family. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33921607, 26103963, 34906470, 38540785). ClinVar contains an entry for this variant (Variation ID: 1042725). Based on the evidence outlined above, the variant was classified as pathogenic.