ClinVar Miner

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

gnomAD frequency: 0.00319  dbSNP: rs1800546
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 41
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000224056 SCV000230833 pathogenic not provided 2018-07-17 criteria provided, single submitter 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
GeneDx RCV000224056 SCV000322438 pathogenic not provided 2022-03-22 criteria provided, single submitter clinical testing Reported as the most common ALDOB pathogenic variant among individuals of European ancestry (Santer et al., 2005); Published functional studies demonstrate A150P decreases substrate affinity and enzyme stability and results in loss of thermostability and significantly lower activity than wild type protein (Esposito et al., 2002; Malay et al., 2002); X-ray crystallography shows extensive structural perturbation at the site of the substitution and in the adjacent loop regions (Malay et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12464284, 15733923, 19768653, 29510902, 27797444, 15880727, 12417303, 3383242, 25333069, 22975760, 18541450, 26937407, 29984853, 31589614, 30609409, 22773061, 31980526, 8096362, 34440436, 34426522)
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000000493 SCV000711745 pathogenic Hereditary fructosuria 2022-06-30 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 approximately half of HFI alleles identified worldwide (Cross and Cox 1989 PMID: 3383242, Malay 2005 PMID: 15733923). In vitro functional studies also provide evidence that the p.Ala150Pro variant impacts protein function (Esposito 2002 PMID: 12417303, Malay 2002 PMID: 12464284, Malay 2005 PMID: 15733923). This variant has been identified in 0.47% (604/126366) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP 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 autosomal recessive manner based upon functional evidence and biallelic occurrence in affected individuals. ACMG/AMP Criteria applied: PM3_Very Strong, PS4_Moderate, PS3_Supporting.
Invitae RCV000000493 SCV000752027 pathogenic Hereditary fructosuria 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 150 of the ALDOB protein (p.Ala150Pro). This variant is present in population databases (rs1800546, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with inherited fructose intolerance (PMID: 3383242, 8096362, 15880727, 18541450, 19768653, 27797444). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 464). 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: 12417303, 12464284). For these reasons, this variant has been classified as Pathogenic.
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).
Fulgent Genetics, Fulgent Genetics RCV000000493 SCV000894461 pathogenic Hereditary fructosuria 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000000493 SCV001163208 pathogenic Hereditary fructosuria 2024-03-30 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000000493 SCV001193927 pathogenic Hereditary fructosuria 2019-11-12 criteria provided, single submitter clinical testing NM_000035.3(ALDOB):c.448G>C(A150P) is classified as pathogenic in the context of hereditary fructose intolerance. Sources cited for classification include the following: PMID 23114028, 11757579, 16406649, 15880727, 18541450, 3383242, 1967768, and 15532022. Classification of NM_000035.3(ALDOB):c.448G>C(A150P) 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.
CeGaT Center for Human Genetics Tuebingen RCV000224056 SCV001249913 pathogenic not provided 2024-03-01 criteria provided, single submitter clinical testing ALDOB: PM3:Very Strong, PS3, PM2:Supporting, PP1
Elsea Laboratory, Baylor College of Medicine RCV000000493 SCV001424273 pathogenic Hereditary fructosuria 2020-04-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000000493 SCV001810255 pathogenic Hereditary fructosuria 2021-07-22 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000000493 SCV002024904 pathogenic Hereditary fructosuria 2022-12-20 criteria provided, single submitter clinical testing
New York Genome Center RCV000000493 SCV002025585 pathogenic Hereditary fructosuria 2020-04-30 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000000493 SCV002061466 pathogenic Hereditary fructosuria 2021-07-16 criteria provided, single submitter clinical testing PS3, PP1, PP3, PM2, PM3
Genetic Services Laboratory, University of Chicago RCV000224056 SCV002064384 pathogenic not provided 2019-11-27 criteria provided, single submitter clinical testing DNA sequence analysis of the ALDOB gene demonstrated a sequence change, c.448G>C, in exon 5 that results in an amino acid change, p.Ala150Pro. This sequence change has been described in the gnomAD database with a population frequency of 0.49%, however, it has not been observed in homozygous state in any individuals (dbSNP rs1800546). This sequence change (alternatively reported as p.Ala149Pro) has previously been described in the homozygous or compound heterozygous states with another pathogenic variant, in individuals with hereditary fructose intolerance (PMID: 3383242, PMID: 27797444, PMID: 22975760, PMID: 26937407, PMID: 20162364) and is one of the most commonly reported ALDOB pathogenic variant in individuals of European ancestry. The p.Ala150Pro change affects a moderately conserved amino acid residue located in a domain of the ALDOB protein that is known to be functional. In vitro functional analyses showed that the p.Ala150Pro substitution has an impact on both substrate affinity and enzyme stability and wild type protein activity is reduced (PMID: 12417303, PMID: 12464284).
Provincial Medical Genetics Program of British Columbia, University of British Columbia RCV000000493 SCV002496385 pathogenic Hereditary fructosuria 2022-01-01 criteria provided, single submitter clinical testing
Mendelics RCV000000493 SCV002517552 pathogenic Hereditary fructosuria 2022-05-04 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251841 SCV002523065 pathogenic See cases 2022-03-28 criteria provided, single submitter clinical testing ACMG classification criteria: PS3, PM3, PP3
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000000493 SCV002767902 pathogenic Hereditary fructosuria 2022-03-31 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hereditary fructose intolerance (MIM#229600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (472 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycolytic domain (NCBI, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and is one of the most common deleterious variants in this gene (ClinVar, PMID: 15880727). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrate that this missense variant results in the complete loss of catalytic activity and efficiency of substrates fructose-1,6-bisphosphate and fructose-1-phosphate (PMID: 12417303). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000000493 SCV004014025 pathogenic Hereditary fructosuria 2023-05-02 criteria provided, single submitter clinical testing PS3, PM2, PP2, PP3, PP4, PP5
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000000493 SCV004046147 pathogenic Hereditary fructosuria criteria provided, single submitter clinical testing This variant (also referred to as p.Ala149Pro in the literature) has been previously reported in the homozygous or compound heterozygous state in individuals with hereditary fructose intolerance (PMID: 3383242, 8096362, 19768653, 15880727, 18541450, 27797444). The c.448G>C (p.Ala150Pro) variant is the most common pathogenic variant in ALDOB (PMID: 15733923). Functional studies show this variant reduces substrate affinity as well as enzyme thermal stability, quaternary structure, and activity (PMID:12417303, 12464284, 15733923). The c.448G>C (p.Ala150Pro) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.3% (874/282528) and is absent in the homozygous state. It is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.448G>C (p.Ala150Pro) variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003415603 SCV004106651 pathogenic ALDOB-related disorder 2024-02-01 criteria provided, single submitter clinical testing The ALDOB c.448G>C variant is predicted to result in the amino acid substitution p.Ala150Pro. This variant, also referred to as p.Ala149Pro in the literature, is one of the most frequently reported causative variants for hereditary fructose intolerance (Cross et al. 1988. PubMed ID: 3383242; Sánchez-Gutiérrez et al. 2002. PubMed ID: 12205126). This variant is reported in 0.49% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000224056 SCV004226612 pathogenic not provided 2022-04-21 criteria provided, single submitter clinical testing PP4, PS3, PS4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000000493 SCV004563889 pathogenic Hereditary fructosuria 2023-10-26 criteria provided, single submitter clinical testing The ALDOB c.448G>C; p.Ala150Pro variant, also reported as Ala149Pro (rs1800546; ClinVar Variation ID: 464), is one of the most common pathogenic ALDOB variants and has been identified in numerous affected individuals both as a homozygote and in trans with other pathogenic ALDOB variants (Cross 1988, Davit-Spraul 2008, Ferri 2012, Li 2018, Valadares 2015). This variant is found in the general population with an overall allele frequency of 0.3% (874/282,528 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.701). Functional studies demonstrate that this variant causes protein instability and loss of enzymatic activity (Esposito 2002, Malay 2002, Malay 2005). Based on the available information, the p.Ala150Pro variant is considered to be pathogenic. References: Cross NC et al. Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation. Cell. 1988;53(6):881-885. PMID: 3383242. Davit-Spraul A et al. Hereditary fructose intolerance: frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France--identification of eight new mutations. Mol Genet Metab. 2008;94(4):443-447. PMID: 18541450. Esposito G et al. Structural and functional analysis of aldolase B mutants related to hereditary fructose intolerance. FEBS Lett. 2002;531(2):152-156. PMID: 12417303. Ferri L et al. Integration of PCR-Sequencing Analysis with Multiplex Ligation-Dependent Probe Amplification for Diagnosis of Hereditary Fructose Intolerance. JIMD Rep. 2012;6:31-37. PMID: 23430936 Li H et al. Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas. Mol Genet Metab. 2018;123(4):428-432. PMID: 29510902. Malay AD et al. Structure of the thermolabile mutant aldolase B, A149P: molecular basis of hereditary fructose intolerance. J Mol Biol. 2005;347(1):135-144. PMID: 15733923. Malay AD et al. The temperature dependence of activity and structure for the most prevalent mutant aldolase B associated with hereditary fructose intolerance. Arch Biochem Biophys. 2002;408(2):295-304. PMID: 12464284. Valadares ER et al. Hereditary fructose intolerance in Brazilian patients. Mol Genet Metab Rep. 2015;4:35-38. PMID: 26937407.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000000493 SCV004807244 likely pathogenic Hereditary fructosuria 2024-03-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV004018526 SCV004885753 pathogenic Inborn genetic diseases 2021-11-24 criteria provided, single submitter clinical testing The c.448G>C (p.A150P) alteration is located in exon 5 (coding exon 4) of the ALDOB gene. This alteration results from a G to C substitution at nucleotide position 448, causing the alanine (A) at amino acid position 150 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.31% (874/282528) total alleles studied. The highest observed frequency was 0.49% (627/128866) of European (non-Finnish) alleles. This mutation (also referred to as A149P) has been reported in the homozygous and compound heterozygous states in many affected patients, and is the most frequent ALDOB mutation with a frequency of up to 64% in various cohorts of patients with hereditary fructose intolerance (Cross, 1988; Santer, 2005; Davit-Spraul, 2008; Coffee, 2010). This amino acid position is not well conserved in available vertebrate species. In vitro functional studies show that protein with the p.A150P mutation demonstrates temperature-dependent structural changes and decreased enzyme activity compared to wild type protein (Esposito, 2002; Malay, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM RCV000000493 SCV000020642 pathogenic Hereditary fructosuria 2008-08-01 no assertion criteria provided literature only
HFI Laboratory at Boston University, Boston University RCV000000493 SCV000067374 pathogenic Hereditary fructosuria no assertion criteria provided clinical testing
DLE - Diagnosticos Laboratoriais Especializados RCV000000493 SCV000077515 pathogenic Hereditary fructosuria no assertion criteria provided clinical testing
GeneReviews RCV000000493 SCV000257571 not provided Hereditary fructosuria no assertion provided literature only One of the six most common HFI variants in US and European populations including Turkey, Spain, Central Europe, France, US, and Italy
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare RCV000000493 SCV000323150 pathogenic Hereditary fructosuria no assertion criteria provided clinical testing
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.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000000493 SCV001132811 pathogenic Hereditary fructosuria 2019-01-29 no assertion criteria provided clinical testing
Natera, Inc. RCV000000493 SCV001462843 pathogenic Hereditary fructosuria 2020-09-16 no assertion criteria provided clinical testing
ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul RCV000000493 SCV001573838 pathogenic Hereditary fructosuria 2021-03-18 no assertion criteria provided literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000224056 SCV001808419 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000224056 SCV001958090 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000224056 SCV001972164 likely pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.