ClinVar Miner

Submissions for variant NM_014639.4(SKIC3):c.4507C>T (p.Arg1503Cys)

gnomAD frequency: 0.00019  dbSNP: rs200067423
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000262565 SCV000341484 uncertain significance not provided 2016-04-14 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000262565 SCV001249413 pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000262565 SCV002310115 uncertain significance not provided 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1503 of the TTC37 protein (p.Arg1503Cys). This variant is present in population databases (rs200067423, gnomAD 0.04%). This missense change has been observed in individual(s) with trichohepatoenteric syndrome (PMID: 28292286, 34093558). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 287653). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282106 SCV002572465 uncertain significance not specified 2022-07-08 criteria provided, single submitter clinical testing Variant summary: TTC37 (SKIC3) c.4507C>T (p.Arg1503Cys) results in a non-conservative amino acid change in 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 5.7e-05 in 282368 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TTC37 causing Trichohepatoenteric Syndrome (5.7e-05 vs 0.00093), allowing no conclusion about variant significance. c.4507C>T has been reported in the literature in two homozygous brothers affected with Trichohepatoenteric Syndrome, with unaffected heterozygous parents and sister (Kinnear_2017). 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. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Revvity Omics, Revvity RCV002291216 SCV003821656 uncertain significance Trichohepatoenteric syndrome 1 2019-01-24 criteria provided, single submitter clinical testing
OMIM RCV002291216 SCV002578252 pathogenic Trichohepatoenteric syndrome 1 2022-10-10 no assertion criteria provided literature only

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