Submissions for variant NM_003322.6(TULP1):c.1471T>C (p.Phe491Leu)

dbSNP: rs121909074

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001074767	SCV001240362	likely pathogenic	Retinal dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092261	SCV001248681	pathogenic	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001092261	SCV002154227	pathogenic	not provided	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 491 of the TULP1 protein (p.Phe491Leu). This variant is present in population databases (rs121909074, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of TULP1-related conditions (PMID: 9462750, 32531858). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7358). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TULP1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TULP1 function (PMID: 26427415). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000007783	SCV003762120	pathogenic	Retinitis pigmentosa 14	2023-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001092261	SCV005327327	likely pathogenic	not provided	2024-03-14	criteria provided, single submitter	clinical testing	Observed multiple times with a second TULP1 variant in unrelated patients with retinal dystrophy referred for genetic testing at GeneDx and reported in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 9462750, 32531858, 36769033); Published functional studies demonstrate that F491L disrupts TULP1 transportation from the ER leading to retinal cell death (PMID: 26987071); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26427415, 33907372, 9462750, 32531858, 31964843, 36769033, 26987071)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782011	SCV005395413	likely pathogenic	Leber congenital amaurosis	2024-09-18	criteria provided, single submitter	clinical testing	Variant summary: TULP1 c.1471T>C (p.Phe491Leu) 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 251428 control chromosomes. c.1471T>C has been reported in the literature in the compound heterozygous or presumed compound heterozygous state in multiple individuals affected with clinical features of Leber Congenital Amaurosis or inherited retinal dystrophy (example, Hagstrom_1998, Weisschuh_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severe protein mislocation, induction of the unfolded protein response, and increased apoptotic rate in vitro and in mouse retinal cells (example, Lobo_2016). The following publications have been ascertained in the context of this evaluation (PMID: 9462750, 26987071, 32531858). ClinVar contains an entry for this variant (Variation ID: 7358). Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000007783	SCV000027984	pathogenic	Retinitis pigmentosa 14	1998-02-01	no assertion criteria provided	literature only