Submissions for variant NM_144596.4(TTC8):c.1382C>T (p.Ala461Val)

gnomAD frequency: 0.00002  dbSNP: rs139195149

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000346459	SCV000389358	uncertain significance	Bardet-Biedl syndrome 8	2018-01-12	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	RCV000394532	SCV000389359	uncertain significance	Retinitis pigmentosa	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001360700	SCV001556630	uncertain significance	Bardet-Biedl syndrome	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 451 of the TTC8 protein (p.Ala451Val). This variant is present in population databases (rs139195149, gnomAD 0.008%). 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: 314802). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	RCV003165848	SCV003865905	uncertain significance	Inborn genetic diseases	2023-01-10	criteria provided, single submitter	clinical testing	The c.1352C>T (p.A451V) alteration is located in exon 13 (coding exon 13) of the TTC8 gene. This alteration results from a C to T substitution at nucleotide position 1352, causing the alanine (A) at amino acid position 451 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004745335	SCV005363603	uncertain significance	TTC8-related disorder	2024-03-10	no assertion criteria provided	clinical testing	The TTC8 c.1382C>T variant is predicted to result in the amino acid substitution p.Ala461Val. This variant is also referred as NM_198310.3:c.1262C>T (p.Ala421Val). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0097% of alleles in individuals of European (Non-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.