ClinVar Genomic variation as it relates to human health

The GALT c.292G>A; p.Asp98Asn variant (rs111033670), is reported in the compound heterozygous state in the literature in individuals affected with galactosemia (Calderon 2007, Tyfield 1999). This variant is reported in ClinVar (Variation ID: 25148), and found in the general population with an overall allele frequency of 0.003% (10/282870 alleles) in the Genome Aggregation Database. The aspartate at codon 98 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.954). Based on available information, this variant is considered to be pathogenic. References: Calderon FR et al. Combination of enzyme analysis, allele-specific PCR and sequencing to detect mutations in the GALT gene. J Inherit Metab Dis. 2007 Oct;30(5):818. PMID: 17876724. Tyfield L et al. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat. 1999;13(6):417-30. PMID: 10408771

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 98 of the GALT protein (p.Asp98Asn). This variant is present in population databases (rs111033670, gnomAD 0.006%). This missense change has been observed in individual(s) with galactosemia (PMID: 10408771, 12595586, 17876724, 22743281). ClinVar contains an entry for this variant (Variation ID: 25148). 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 GALT protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Variant summary: The GALT c.292G>A (p.Asp98Asn) variant involves the alteration of a conserved nucleotide, is located in UDP-alpha-D-glucose binding region and is involved in interaction with substrate (UniProt, Facchiano_2010). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 8/277204 control chromosomes (gnomAD) at a frequency of 0.0000289, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALT variant (0.0028868). This variant has been reported in multiple patients with galactosemia in homozygous as well as in compound heterozygous state with other pathogenic variants (Tyfield, Webb_2003, Schulpis_2017, ARUP). Enzymatic analysis of the homozygote showed no activity, strongly suggesting that this variant is defective. Another missense change at the same codon (p.Asp98His) has been classified as pathogenic by our lab, suggesting functional importance of this codon. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); 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: 28644047, 10408771, 17876724, 22743281, 20008339, 27363831, 31358168, 30718057, 34302356, 12595586)

NM_000155.3(GALT):c.292G>A(D98N) is a missense variant classified as likely pathogenic in the context of galactosemia. D98N has been observed in cases with relevant disease (PMID: 31358168, 28644047, 17876724, 27363831, 30718057, 12595586). Functional assessments of this variant are not available in the literature. D98N has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000155.3(GALT):c.292G>A(D98N) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.