Submissions for variant NM_003193.5(TBCE):c.1465C>A (p.Leu489Ile)

gnomAD frequency: 0.00064  dbSNP: rs143917509

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000303019	SCV000333633	uncertain significance	not provided	2015-08-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000332713	SCV000355655	uncertain significance	Hypoparathyroidism-retardation-dysmorphism syndrome	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.
Invitae	RCV000303019	SCV001542716	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 489 of the TBCE protein (p.Leu489Ile). This variant is present in population databases (rs143917509, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TBCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 282266). 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 not expected to disrupt TBCE protein function. 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.
GeneDx	RCV000303019	SCV002513029	uncertain significance	not provided	2022-04-15	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in a family with primary hyperparathyroidism (Cetani et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31486992)
CeGaT Center for Human Genetics Tuebingen	RCV000303019	SCV004126137	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TBCE: BP4