Submissions for variant NM_003322.6(TULP1):c.1376T>C (p.Ile459Thr)

gnomAD frequency: 0.00129  dbSNP: rs121909075

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174738	SCV000226099	uncertain significance	not provided	2014-08-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000174738	SCV001092079	likely benign	not provided	2024-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000174738	SCV002072830	likely pathogenic	not provided	2024-03-14	criteria provided, single submitter	clinical testing	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: 29843741, 27440997, 32037395, 24154662, 38450199)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222423	SCV002500628	likely benign	not specified	2023-05-30	criteria provided, single submitter	clinical testing	Variant summary: TULP1 c.1376T>C (p.Ile459Thr) results in a non-conservative amino acid change located in the Tubby, C-terminal domain (IPR000007) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251456 control chromosomes, predominantly at a frequency of 0.0039 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TULP1 causing Leber Congenital Amaurosis phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin.c.1376T>C has been reported in the literature in individuals affected with Retinitis Pigmentosa (e.g. Wang_2014, Zampaglione_2020). These reports do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. 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: 24154662, 32037395). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004537371	SCV004720205	likely benign	TULP1-related disorder	2023-07-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).