ClinVar Miner

Submissions for variant NM_000035.4(ALDOB):c.524C>A (p.Ala175Asp) (rs76917243)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000352944 SCV000230834 pathogenic not provided 2017-10-03 criteria provided, single submitter clinical testing
GeneDx RCV000352944 SCV000330017 pathogenic not provided 2018-02-21 criteria provided, single submitter clinical testing The A175D variant in the ALDOB gene has been observed numerous times (also reported as A174D due to alternate nomenclature), either in the homozygous or in the compound heterozygous state with another pathogenic variant, in individuals with hereditary fructose intolerance (Cross et al., 1990; Ferri et al., 2012; Valadares et al., 2015). The A175D variant is observed in 18/10,146 alleles (0.17%) from individuals of Ashkenazi Jewish background, and 94/276,618 global alleles (0.034%) with no homozygous control individuals reported, in large population cohorts (Lek et al., 2016). The A175D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect, and structural studies indicate that the A175D variant may alter the structural and functional integrity of the aldolase B enzyme by introducing a polar residue into a hydrophobic environment (Esposito et al., 2002). We interpret A175D as a pathogenic variant.
Counsyl RCV000000494 SCV000485187 pathogenic Hereditary fructosuria 2016-03-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000000494 SCV000693983 pathogenic Hereditary fructosuria 2017-02-10 criteria provided, single submitter clinical testing 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.
Invitae RCV000000494 SCV000812921 pathogenic Hereditary fructosuria 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 175 of the ALDOB protein (p.Ala175Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs76917243, ExAC 0.05%). This variant has been observed as homozygous or on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with hereditary fructose intolerance (PMID: 1967768, 15880727, 18541450, 26937407). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as Ala174Asp in the literature. ClinVar contains an entry for this variant (Variation ID: 465). Experimental studies have shown that this missense change reduces ALDOB protein stability (PMID: 12417303, 10625657). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000000494 SCV000894460 pathogenic Hereditary fructosuria 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000000494 SCV000020643 pathogenic Hereditary fructosuria 2008-08-01 no assertion criteria provided literature only
HFI Laboratory at Boston University,Boston University RCV000000494 SCV000067375 pathogenic Hereditary fructosuria no assertion criteria provided clinical testing
DLE - Diagnosticos Laboratoriais Especializados RCV000000494 SCV000077516 pathogenic Hereditary fructosuria no assertion criteria provided clinical testing
GeneReviews RCV000000494 SCV000257572 pathogenic Hereditary fructosuria 2015-10-07 no assertion criteria provided literature only

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