ClinVar Genomic variation as it relates to human health

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 858 of the SLC4A1 protein (p.Ala858Asp). This variant is present in population databases (rs121912751, gnomAD 0.06%). This missense change has been observed in individuals with autosomal dominant and autosomal recessive distal renal tubular acidosis (dRTA) and hemolytic anemia (PMID: 20151848, 20799361, 22126643, 10926824). Individuals heterozygous for this variant alone have incomplete dRTA and can be asymptomatic until further clinical evaluation (PMID: 10926824, 22126643) while individuals that are either homozygous or compound heterozygous with other pathogenic variants have a more severe complete dRTA and/or hemolytic anemia (PMID: 22126643, 20799361, 10926824). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17771). 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 expected to disrupt SLC4A1 protein function. Experimental studies have shown that this missense change affects SLC4A1 function (PMID: 19289107, 20151848). For these reasons, this variant has been classified as Pathogenic.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.70). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017771). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in multiple similarly affected unrelated individuals (PMID: 22126643). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

The observed missense c.782C>T(p.Thr261Ile) variant in GCDH gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0.001% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Uncertain significance (multiple submissions). Multiple lines of computational evidence (Polyphen - probably damaging , SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 261 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).