ClinVar Genomic variation as it relates to human health

NM_000035.3(ALDOB):c.524C>A(A175D) is classified as pathogenic in the context of hereditary fructose intolerance. Sources cited for classification include the following: PMID 15880727, 18541450, 1967768, 12417303 and 20033295. Classification of NM_000035.3(ALDOB):c.524C>A(A175D) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(A174D); This variant is associated with the following publications: (PMID: 32709737, 20848650, 12205126, 22975760, 1967768, 26937407, 10024431, 15532022, 32860008, 31589614, 31980526, 34426522, 33726816, 31319225, 34162028, 12417303, 23430936, 15880727, 18541450, 36007526)

The p.Ala175Asp (NM_000035.3 c.524C>A) (legacy p.Ala174Asp) variant in ALDOB has been reported in atleast 5 homozygous and 13 compound heterozygous individuals with hereditary fructose intolerance (Cross 1990 PMID: 1967768, Ferri 2012 PMID: 23430936, and Valdares 2015 PMID: 26937407). It has also been identified in 0.177% (18/10146) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs118204424, rs76917243), and has been reported in ClinVar (Variation ID#465) as pathogenic by multiple laboratories. In vitro functional studies provide evidence that the p.Ala175Asp variant impacts protein function (Esposito 2002 PMID: 12417303). This variant has been identified in 0.177% (18/10146) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs118204424, rs76917243), though this frequency is low enough to be consistent with a recessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala175Asp variant meets criteria to be classified as pathogenic for autosomal recessive hereditary fructose intolerance. ACMG/AMP criteria applied: PM3_VeryStrong, PP3, PS3_Supporting.

Variant summary: The ALDOB c.524C>A (p.Ala175Asp) variant involves the alteration of a conserved nucleotide and results in a replacement of a small size and hydrophobic Alanine (A) with a medium size and acidic Aspartic acid (D) located in the Fructose-bisphosphate aldolase domain. 5/5 in silico tools predict a damaging outcome for this substitution. This variant was found in 40/121278 control chromosomes at a frequency of 0.0003298, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALDOB variant (0.0044721). It was reported in several Hereditary Fructose Intolerance patients in homozygosity or in compound heterozygosity with other potentially pathogenic ALDOB variants suggesting pathogenicity. A functional study reported the variant to result in insoluble form of the ALDB protein when expressed in E.Coli indicating that structural perturbations produced by the variant affects the overall integrity of the enzyme. Moreover, the variant is known to be a common disease causing mutation accounting for about 70-80% of all HFI alleles worldwide (PMID: 20848650). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

ACMG classification criteria: PS3, PS4, PM2, PM3, PP3

PS4, PS3, PM2, PP3, PP5

This variant (also referred to as p.Ala174Asp in the literature) has been previously reported either in the homozygous or in the compound heterozygous state in patients with hereditary fructose intolerance (PMID: 12205126, 15880727, 18541450, 26937407). The c.524C>A (p.Ala175Asp) variant is the second most common pathogenic variant in ALDOB (PMID: 15880727). In vitro testing of this variant as a recombinant protein suggested that it may affect the protein's structural stability (PMID: 10625657, 12417303). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.035% (99/282292) and is absent in the homozygous state. The c.524C>A (p.Ala175Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.524C>A (p.Ala175Asp) variant is classified as Pathogenic.

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 175 of the ALDOB protein (p.Ala175Asp). This variant is present in population databases (rs76917243, gnomAD 0.2%). This missense change has been observed in individual(s) with hereditary fructose intolerance (PMID: 1967768, 15880727, 18541450, 26937407). It has also been observed to segregate with disease in related individuals. This variant is also known as Ala174Asp. ClinVar contains an entry for this variant (Variation ID: 465). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ALDOB function (PMID: 10625657, 12417303). For these reasons, this variant has been classified as Pathogenic.

The c.524C>A (p.A175D) alteration is located in exon 5 (coding exon 4) of the ALDOB gene. This alteration results from a C to A substitution at nucleotide position 524, causing the alanine (A) at amino acid position 175 to be replaced by an aspartic acid (D). Based on data from gnomAD, the A allele has an overall frequency of 0.04% (99/282292) total alleles studied. The highest observed frequency was 0.16% (17/10362) of Ashkenazi Jewish alleles. This alteration has been reported in multiple unrelated patients with hereditary fructose intolerance and is one of the most common mutations in the U.S. and Europe (Cross, 1990; Sánchez-Gutiérrez, 2002; Santer, 2005; Caciotti, 2008; Davit-Spraul, 2008; Valadares, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

The ALDOB c.524C>A variant is predicted to result in the amino acid substitution p.Ala175Asp. This variant has been reported to be one of the most common causative variants for hereditary fructose intolerance (for example see: Cross and Cox. 1990. PubMed ID: 2349937; Santer et al. 2005. PubMed ID: 15880727; Davit-Spraul et al. 2008. PubMed ID: 18541450; Valadares et al. 2015. PubMed ID: 26937407). Note, this variant is also referred to as A174D in some literature. This variant is reported in 0.16% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.

One of the six most common HFI variants in US and European populations including Turkey, Spain, Central Europe, France, US, and Italy