Submissions for variant NM_000361.3(THBD):c.763G>C (p.Ala255Pro)

gnomAD frequency: 0.00001  dbSNP: rs1276712753

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003727966	SCV004535277	uncertain significance	not provided	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 255 of the THBD protein (p.Ala255Pro). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with THBD-related conditions. ClinVar contains an entry for this variant (Variation ID: 988131). 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 THBD protein function with a negative predictive value of 80%. 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.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328106	SCV001449453	uncertain significance	Atypical hemolytic-uremic syndrome	2019-06-11	no assertion criteria provided	clinical testing	This individual is heterozygous for the c.763G>C variant in the THBD gene, which results in the amino acid substitution of alanine to proline at residue 255, p.(Ala255Pro). To our knowledge, this variant has not been previously reported in the literature or any disease specific databases, including the Database of complement gene variants (https://www.complement-db.org/home.php), to be a disease causing variant. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.0015% (3 out of 204 426 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster suggest that this variant does not affect protein function and is likely to be benign. However, this analysis alone cannot be used to exclude pathogenicity. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. (Evidence used: PM2, BP4).