ClinVar Genomic variation as it relates to human health

The observed missense variant c.2573C>A(p.Ala858Asp) in SLC4A1 gene has been reported previously in homozygous, compound heterozygous and heterozygous state in individuals with distal renal tubular acidosis (Shmukler BE, et al., 2010, Ungsupravate D, et al., 2010, Walsh S, et al., 2009). Experimental studies have shown that this missense change affects SLC4A1 function (Ungsupravate D, et al., 2010, Walsh S, et al., 2009). 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 c.2573C>A variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The amino acid Alanine at position 858 is changed to a Aspartic acid changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The reference amino acid change p.Ala858Asp in SLC4A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with distal renal tubular acidosis 4 with haemolytic anaemia (MIM#611590), cryohydrocytosis (MIM#185020), distal renal tubular acidosis (MIM#1179800), ovalocytosis, SA type (MIM#166900) and hereditary spherocytosis (MIM#61265) (PMID: 27058983). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene predominantly lead to autosomal dominant conditions, where biallelic variants result in the more severe phenotype, with no correlation in terms of variant types or location (PMID: 27058983). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to aspartic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (18 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in multiple homozygous and compound heterozygous individuals with distal renal tubular acidosis with haemolytic anaemia. Heterozygous individuals had hypochromia microcytosis and mild acanthocytosis (ClinVar, PMID: 22126643, PMID: 31959358). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign