ClinVar Miner

Submissions for variant NM_003322.6(TULP1):c.931C>T (p.Arg311Trp)

gnomAD frequency: 0.00001  dbSNP: rs373519519
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000987688 SCV001137105 likely pathogenic Leber congenital amaurosis 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001301120 SCV001490280 pathogenic not provided 2023-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 311 of the TULP1 protein (p.Arg311Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 26856745; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 802210). 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 80%. This variant disrupts the p.Arg311 amino acid residue in TULP1. Other variant(s) that disrupt this residue have been observed in individuals with TULP1-related conditions (PMID: 21792230, 28559085; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
3billion RCV001809877 SCV002058492 likely pathogenic Retinitis pigmentosa 14 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TULP1 related disorder (PMID:26856745, PS1_P). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001065758, PMID:21792230, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.885, 3CNET: 0.924, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271603 SCV002556077 uncertain significance not specified 2023-08-11 criteria provided, single submitter clinical testing Variant summary: TULP1 c.931C>T (p.Arg311Trp) 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 allele was found at a frequency of 8e-06 in 250642 control chromosomes. c.931C>T has been reported in the literature in two compound heterozygous brothers affected with Leber Congenital Amaurosis, with one unaffected heterozygous sister and parent (Tajiguli_2016). The variant was also found in one heterozygous individual with Retinitis Pigmentosa (Ma_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Additionally, other variant at the Arg311 residue has been reported in cases with Retinitis Pigmentosa (p.Arg311Gln), suggesting that this codon may be functionally important. Further evidence however is needed to establish the pathogenicity of p.Arg311Gln. The following publications have been ascertained in the context of this evaluation (PMID: 26856745, 33691693). Three ClinVar submitters have assessed the variant since 2014 (all Likely pathogenic). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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