Submissions for variant NM_003322.6(TULP1):c.1486G>A (p.Ala496Thr)

gnomAD frequency: 0.00107  dbSNP: rs141980901

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000591717	SCV000705036	likely benign	not specified	2017-01-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000086070	SCV001098633	likely benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000086070	SCV001154732	uncertain significance	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001156199	SCV001317685	uncertain significance	Retinitis pigmentosa	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001156200	SCV001317686	uncertain significance	Leber congenital amaurosis 15	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000591717	SCV002103689	benign	not specified	2022-03-03	criteria provided, single submitter	clinical testing	Variant summary: TULP1 c.1486G>A (p.Ala496Thr) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00086 in 251230 control chromosomes, predominantly at a frequency of 0.0027 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 5.4 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 Latino origin. c.1486G>A has been reported in the literature as a heterozygous variant in at-least one in individual affected with Leber Congenital Amaurosis, who had an alternate molecular basis of disease described below (example, El Shamieh_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. The co-occurrence with another reported pathogenic RP1 gene variant is, homozygous c.2391_2392delAA, p.Asp799*, in the proband from a consanguineous family, providing supporting evidence for a benign role (El Shamieh_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as benign.
Retina International	RCV000086070	SCV000118214	not provided	not provided		no assertion provided	not provided
Clinical Genetics, Academic Medical Center	RCV000086070	SCV001925097	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000086070	SCV001964545	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734646	SCV005352656	likely benign	TULP1-related disorder	2024-08-05	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).