Submissions for variant NM_144596.4(TTC8):c.1042T>C (p.Phe348Leu)

gnomAD frequency: 0.00002  dbSNP: rs200086953

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001116278	SCV001274329	uncertain significance	Bardet-Biedl syndrome 8	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001116279	SCV001274330	uncertain significance	Retinitis pigmentosa	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001371670	SCV001568242	uncertain significance	Bardet-Biedl syndrome	2022-08-23	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 338 of the TTC8 protein (p.Phe338Leu). This variant is present in population databases (rs200086953, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TTC8-related conditions. ClinVar contains an entry for this variant (Variation ID: 884952). 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: "Benign"; 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.
Ambry Genetics	RCV002556291	SCV003595732	uncertain significance	Inborn genetic diseases	2021-12-14	criteria provided, single submitter	clinical testing	The c.1012T>C (p.F338L) alteration is located in exon 10 (coding exon 10) of the TTC8 gene. This alteration results from a T to C substitution at nucleotide position 1012, causing the phenylalanine (F) at amino acid position 338 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
New York Genome Center	RCV001116278	SCV003925092	uncertain significance	Bardet-Biedl syndrome 8	2022-03-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003898109	SCV004713526	uncertain significance	TTC8-related condition	2024-02-14	criteria provided, single submitter	clinical testing	The TTC8 c.1042T>C variant is predicted to result in the amino acid substitution p.Phe348Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.