ClinVar Miner

Submissions for variant NM_000035.4(ALDOB):c.448G>C (p.Ala150Pro) (rs1800546)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000000493 SCV000323150 pathogenic Hereditary fructosuria no assertion criteria provided clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224056 SCV000280999 pathogenic not provided 2014-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000000493 SCV000485176 pathogenic Hereditary fructosuria 2015-12-29 criteria provided, single submitter clinical testing
DLE - Diagnosticos Laboratoriais Especializados RCV000000493 SCV000077515 pathogenic Hereditary fructosuria no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224056 SCV000230833 pathogenic not provided 2018-07-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000000493 SCV000894461 pathogenic Hereditary fructosuria 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000224056 SCV000322438 pathogenic not provided 2017-07-10 criteria provided, single submitter clinical testing The A150P variant is the most common ALDOB pathogenic variant among individuals of European ancestry; it has been observed numerous times (also reported as A149P 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., 1988; Santer et al., 2005; Davit-Spraul et al., 2008). The NHLBI Exome Sequencing Project reports A150P was observed in 43/8600 alleles from individuals of European background; no individuals in this control population were homozygous for this variant. This substitution occurs at a position that is conserved in mammals. In vitro functional analyses have indicated that the A150P substitution decreases substrate affinity and enzyme stability; additionally, ALDOB protein harboring this substitution showed loss of thermostability and significantly lower activity than wild type protein (Esposito et al., 2002; Malay et al., 2002). X-ray crystallography shows that this variant results in extensive structural perturbation at the site of the substitution and in the adjacent loop regions (Malay et al., 2005). We interpret A150P as a pathogenic variant.
GeneReviews RCV000000493 SCV000257571 pathogenic Hereditary fructosuria 2015-10-07 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000000493 SCV000840266 not provided Hereditary fructosuria no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
HFI Laboratory at Boston University,Boston University RCV000000493 SCV000067374 pathogenic Hereditary fructosuria no assertion criteria provided clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000000493 SCV000476066 pathogenic Hereditary fructosuria 2018-05-17 criteria provided, single submitter clinical testing The ALDOB c.448G>C (p.Ala150Pro) variant is well-documented as one of the most common variants among patients with hereditary fructose intolerance in European and North American populations (Baker et al. 2015). Across a small selection of the available literature, the p.Ala150Pro variant was identified in a homozygous state in 44 patients, in a compound heterozygous state in 33 patients, and in a heterozygous state in three unaffected family members of a patient (Cross et al. 1988; Coffee et al. 2010). Control data are not reported in these studies for this variant, which is found at a frequency of 0.00895 in the European population from the 1000 Genomes Project. The ALDOB p.Ala150Pro variant protein, extracted from liver and intestinal tissues from a homozygous patient, showed a profound reduction in substrate affinity and specific activity when compared with control subjects (Cox et al. 1983), and in vitro functional studies of ALDOB variants demonstrated that the p.Ala150Pro variant protein was highly unstable with no detectable residual enzyme activity (Esposito et al. 2002). Based on the collective evidence, the p.Ala150Pro variant is classified as pathogenic for hereditary fructose intolerance. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000000493 SCV000693962 pathogenic Hereditary fructosuria 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The ALDOB c.448G>C (p.Ala150Pro) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 328/121396 control chromosomes at a frequency of 0.0027019, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALDOB variant (0.0044721). The variant of interest has been reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000000493 SCV000752027 pathogenic Hereditary fructosuria 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 150 of the ALDOB protein (p.Ala150Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs1800546, ExAC 0.4%). This variant is known as the most common mutation in the ALDOB gene. It has been reported as homozygous or in combination with other ALDOB variants in many individuals affected with inherited fructose intolerance and in families with evidence of disease co-segregation (PMID: 3383242, 8096362, 19768653, 15880727, 18541450, 27797444). This variant is also known as p.Ala149Pro in the literature. ClinVar contains an entry for this variant (Variation ID: 464). Experimental studies have shown that this missense change reduces substrate affinity as well as enzyme stability and activity (PMID: 12417303, 12464284). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000000493 SCV000711745 pathogenic Hereditary fructosuria 2018-03-21 criteria provided, single submitter clinical testing The p.Ala150Pro variant in ALDOB (frequently referred to as p.Ala149Pro) is the most common hereditary fructose intolerance (HFI) allele, accounting for approxi mately half of HFI alleles identified worldwide (Cross 1988, Cross and Cox 1989, Malay 2005). In vitro functional studies also provide evidence that the p.Ala15 0Pro variant impacts protein function (Esposito 2002, Malay 2002, Malay 2005). T his variant has been identified in 0.47% (604/126366) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSN P rs1800546). Although it has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for HFI in an autosom al recessive manner based upon functional evidence and biallelic occurrence in a ffected individuals. ACMG/AMP Criteria applied: PM3_Very Strong, PS4_Moderate, P S3_Supporting
OMIM RCV000000493 SCV000020642 pathogenic Hereditary fructosuria 2008-08-01 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000000493 SCV000803454 pathogenic Hereditary fructosuria 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Pathogenic, for Fructose intolerance, hereditary, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PMID:18541450) (PMID:15880727) (PMID:16406649). PS4-Moderate => Recurrent mutation, found in various HFI patients from unrelated pedigrees. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect. Severe reduction of aldolase activity towards fructose-1-phosphate (F-1-P) and fructose-1,6-bisphosphate (F-1,6-P2) measured in hepatic biopsies. In vitro expression studies confirm that the recombinant enzyme has defective activity (PMID:12417303) (PMID:12205126). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:3383242).

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