ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect with this variant resulting in significantly reduced enzyme stability and activity compared to wildtype (Diez-Fernandez et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26913920, 34426522, 32381389, 32809955, 32553838, 25834911, 36464834, 36411877, 33473334)

A Heterozygous Missense variant c.721G>A in Exon 6 of the CA5A gene that results in the amino acid substitution p.Glu241Lys was identified. The observed variant has a maximum allele frequency of 0.00035/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic(Variant ID 388645). Published functional studies demonstrate a damaging effect with this variant resulting in significantly reduced enzyme stability and activity compared to wildtype. This variant has been previously reported by Diez Fernandaz et al., 2006. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.

This variant is present in population databases (rs563971993, gnomAD 0.3%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CA5A function (PMID: 26913920). 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 CA5A protein function. ClinVar contains an entry for this variant (Variation ID: 388645). This missense change has been observed in individuals with carbonic anhydrase VA deficiency (PMID: 26913920, 32381389, 33473334; Invitae). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 241 of the CA5A protein (p.Glu241Lys).

The missense variant c.721G>Ap.Glu241Lys in CA5A gene has been reported in homozygous state in individuals with Mitochondrial carbonic anhydrase VA deficiency Konanki R, et al., 2020. Experimental studies have shown that this missense change affects CA5A function Diez-Fernandez C, et al., 2016. The variant is reported with 0.03% allele frequency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Glutamic acid at position 241 is changed to a Lysine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Glu241Lys in CA5A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Recurrent variant found in majority of affected persons from the Indian subcontinent.