ClinVar Genomic variation as it relates to human health
NM_000035.4(ALDOB):c.448G>C (p.Ala150Pro)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000035.4(ALDOB):c.448G>C (p.Ala150Pro)
Variation ID: 464 Accession: VCV000000464.73
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q31.1 9: 101427574 (GRCh38) [ NCBI UCSC ] 9: 104189856 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 24, 2015 May 1, 2024 Mar 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000035.4:c.448G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000026.2:p.Ala150Pro missense NC_000009.12:g.101427574C>G NC_000009.11:g.104189856C>G NG_012387.1:g.13207G>C LRG_1244:g.13207G>C LRG_1244t1:c.448G>C LRG_1244p1:p.Ala150Pro P05062:p.Ala150Pro - Protein change
- A150P
- Other names
- NM_000035.3(ALDOB):c.448G>C(p.Ala150Pro)
- Canonical SPDI
- NC_000009.12:101427573:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00180 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00141
1000 Genomes Project 0.00180
Trans-Omics for Precision Medicine (TOPMed) 0.00268
Exome Aggregation Consortium (ExAC) 0.00270
The Genome Aggregation Database (gnomAD), exomes 0.00295
The Genome Aggregation Database (gnomAD) 0.00319
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ALDOB | - | - |
GRCh38 GRCh37 |
506 | 545 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (29) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV000000493.51 | |
Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000224056.34 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 28, 2022 | RCV002251841.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV003415603.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2021 | RCV004018526.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Hereditary fructosuria
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803454.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Apr 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: yes, no
Allele origin:
germline
|
Elsea Laboratory, Baylor College of Medicine
Accession: SCV001424273.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Observation 1:
Sex: female
Testing laboratory: Org: 1006
Observation 2:
Sex: male
Testing laboratory: Org: 1006
|
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Pathogenic
(Nov 27, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002064384.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Jan 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary fructosuria
Affected status: yes
Allele origin:
germline
|
Provincial Medical Genetics Program of British Columbia, University of British Columbia
Accession: SCV002496385.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
Sex: male
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Pathogenic
(Mar 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523065.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS3, PM3, PP3
Clinical Features:
Seizure (present) , Neurodevelopmental abnormality (present) , Hemimegalencephaly (present) , Abnormal cerebral cortex morphology (present) , Abnormality of mental function (present)
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Pathogenic
(May 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004014025.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PS3, PM2, PP2, PP3, PP4, PP5
|
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Pathogenic
(Dec 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024904.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000752027.8
First in ClinVar: Apr 09, 2018 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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ALDOB-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004106651.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249913.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Comment:
ALDOB: PM3:Very Strong, PS3, PM2:Supporting, PP1
Number of individuals with the variant: 9
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Pathogenic
(Jun 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary fructosuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711745.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004885753.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Oct 02, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000280999.2
First in ClinVar: Jun 08, 2016 Last updated: Mar 08, 2017 |
|
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Pathogenic
(Aug 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000693962.1
First in ClinVar: Mar 18, 2017 Last updated: Mar 18, 2017 |
Comment:
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. … (more)
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. (less)
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Pathogenic
(Jul 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230833.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 29
Sex: mixed
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894461.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Pathogenic
(May 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000476066.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163208.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
|
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Pathogenic
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193927.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810255.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
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Pathogenic
(Apr 30, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002025585.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
Clinical Features:
Seizure (present) , Autism (present) , Intellectual disability, moderate (present) , Global developmental delay (present) , Attention deficit hyperactivity disorder (present)
Secondary finding: no
|
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Pathogenic
(Jul 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061466.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PP1, PP3, PM2, PM3
|
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Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002517552.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
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Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary fructosuria
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767902.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322438.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
FRUCTOSE INTOLERANCE, HEREDITARY
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046147.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Apr 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226612.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PS3, PS4
Number of individuals with the variant: 5
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Pathogenic
(Oct 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563889.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Mar 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807244.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
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HFI Laboratory at Boston University, Boston University
Accession: SCV000067374.1
First in ClinVar: Mar 18, 2017 Last updated: Mar 18, 2017 |
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Pathogenic
(Aug 01, 2008)
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no assertion criteria provided
Method: literature only
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FRUCTOSE INTOLERANCE, HEREDITARY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020642.3
First in ClinVar: Apr 04, 2013 Last updated: May 04, 2020 |
Comment on evidence:
Cross et al. (1988) reported the first identification of a molecular lesion in the ALDOB gene in hereditary fructose intolerance (HFI; 229600). A G-to-C transversion … (more)
Cross et al. (1988) reported the first identification of a molecular lesion in the ALDOB gene in hereditary fructose intolerance (HFI; 229600). A G-to-C transversion in exon 5 of the ALDOB gene created a new recognition site for the restriction enzyme AhaII and resulted in an ala149-to-pro (A149P) substitution within a region critical for substrate binding. Utilizing this novel restriction site and the polymerase chain reaction (PCR), Cross et al. (1988) showed that the patient was homozygous. Three other patients with hereditary fructose intolerance unrelated to the original patient were found to have the same mutation; 2 were homozygous and 1 was compound heterozygous with another mutation in the ALDOB gene. Cross and Cox (1989) used allele-specific oligonucleotide probes to detect the A149P mutation in other pedigrees. They found the same mutation in all 12 British patients examined. Diagnosis of both homozygotes and heterozygotes could be achieved by specific amplification of DNA derived from mouthwash samples followed by hybridization to allele-specific oligonucleotides. In a study of patients with fructose intolerance drawn widely from Europe and the U.S., Cross et al. (1990) found the A149P mutation in 67% of alleles tested. The mutation was significantly more common in patients from northern than from southern Europe. Brooks and Tolan (1993) studied the possible origin of the A149P mutation, which accounts for 57% of fructose intolerance chromosomes. In 15 homozygotes they found absolute linkage disequilibrium between the A149P mutation and a particular 2-site RFLP, suggesting a single origin and founder effect. Dursun et al. (2001) screened 13 Turkish patients with hereditary fructose intolerance for 3 common mutations. Nine of the patients were homozygous for the A149P mutation, which corresponded to a frequency of about 55%. Davit-Spraul et al. (2008) identified the A149P mutation, which they referred to as ALA150PRO (A150P), in 64% of mutant alleles from 162 patients from 92 families with hereditary fructose intolerance. Most of the patients were French. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hereditary fructosuria
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000323150.1
First in ClinVar: Oct 23, 2016 Last updated: Oct 23, 2016 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
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DLE - Diagnosticos Laboratoriais Especializados
Accession: SCV000077515.1
First in ClinVar: Mar 18, 2017 Last updated: Mar 18, 2017 |
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Pathogenic
(Jan 29, 2019)
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no assertion criteria provided
Method: clinical testing
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Hereditary fructosuria
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001132811.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Fructose intolerance
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001462843.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Mar 18, 2021)
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no assertion criteria provided
Method: literature only
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Hereditary fructosuria
Affected status: yes
Allele origin:
unknown
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ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul
Accession: SCV001573838.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808419.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958090.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001972164.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Hereditary fructosuria
Affected status: unknown
Allele origin:
paternal
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GenomeConnect, ClinGen
Accession: SCV000840266.1
First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Premature birth (present) , Prenatal maternal abnormality (present) , Failure to thrive (present) , Short stature (present) , Abnormality of the neck (present) , Abnormality … (more)
Premature birth (present) , Prenatal maternal abnormality (present) , Failure to thrive (present) , Short stature (present) , Abnormality of the neck (present) , Abnormality of eye movement (present) , Hip dysplasia (present) , Abnormality of cardiovascular system morphology (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2017-12-04
Testing laboratory interpretation: Pathogenic
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not provided
(-)
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no classification provided
Method: literature only
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Hereditary fructosuria
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000257571.3
First in ClinVar: Dec 24, 2015 Last updated: Oct 01, 2022 |
Comment:
One of the six most common HFI variants in US and European populations including Turkey, Spain, Central Europe, France, US, and Italy
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Hereditary Fructose Intolerance. | Adam MP | - | 2021 | PMID: 26677512 |
Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas. | Li H | Molecular genetics and metabolism | 2018 | PMID: 29510902 |
Hereditary fructose intolerance mimicking a biochemical phenotype of mucolipidosis: A review of the literature of secondary causes of lysosomal enzyme activity elevation in serum. | Ferreira CR | American journal of medical genetics. Part A | 2017 | PMID: 27797444 |
Hereditary fructose intolerance in Brazilian patients. | Valadares ER | Molecular genetics and metabolism reports | 2015 | PMID: 26937407 |
Integration of PCR-Sequencing Analysis with Multiplex Ligation-Dependent Probe Amplification for Diagnosis of Hereditary Fructose Intolerance. | Ferri L | JIMD reports | 2012 | PMID: 23430936 |
Fatty liver disease and hypertransaminasemia hiding the association of clinically silent Duchenne muscular dystrophy and hereditary fructose intolerance. | Paolella G | Italian journal of pediatrics | 2012 | PMID: 23114028 |
Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population. | Coffee EM | Journal of inherited metabolic disease | 2010 | PMID: 20033295 |
Secondary disorders of glycosylation in inborn errors of fructose metabolism. | Quintana E | Journal of inherited metabolic disease | 2009 | PMID: 19768653 |
Hereditary fructose intolerance: frequency and spectrum mutations of the aldolase B gene in a large patients cohort from France--identification of eight new mutations. | Davit-Spraul A | Molecular genetics and metabolism | 2008 | PMID: 18541450 |
Aldolase B mutations and prevalence of hereditary fructose intolerance in a Polish population. | Gruchota J | Molecular genetics and metabolism | 2006 | PMID: 16406649 |
The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. | Santer R | Human mutation | 2005 | PMID: 15880727 |
Structure of the thermolabile mutant aldolase B, A149P: molecular basis of hereditary fructose intolerance. | Malay AD | Journal of molecular biology | 2005 | PMID: 15733923 |
Six novel alleles identified in Italian hereditary fructose intolerance patients enlarge the mutation spectrum of the aldolase B gene. | Esposito G | Human mutation | 2004 | PMID: 15532022 |
The temperature dependence of activity and structure for the most prevalent mutant aldolase B associated with hereditary fructose intolerance. | Malay AD | Archives of biochemistry and biophysics | 2002 | PMID: 12464284 |
Structural and functional analysis of aldolase B mutants related to hereditary fructose intolerance. | Esposito G | FEBS letters | 2002 | PMID: 12417303 |
Molecular analysis of the aldolase B gene in patients with hereditary fructose intolerance from Spain. | Sánchez-Gutiérrez JC | Journal of medical genetics | 2002 | PMID: 12205126 |
Mutation analysis in Turkish patients with hereditary fructose intolerance. | Dursun A | Journal of inherited metabolic disease | 2001 | PMID: 11757579 |
Association of the widespread A149P hereditary fructose intolerance mutation with newly identified sequence polymorphisms in the aldolase B gene. | Brooks CC | American journal of human genetics | 1993 | PMID: 8096362 |
Molecular analysis of aldolase B genes in hereditary fructose intolerance. | Cross NC | Lancet (London, England) | 1990 | PMID: 1967768 |
Molecular analysis of aldolase B genes in the diagnosis of hereditary fructose intolerance in the United Kingdom. | Cross NC | The Quarterly journal of medicine | 1989 | PMID: 2623136 |
Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation. | Cross NC | Cell | 1988 | PMID: 3383242 |
Isolation and characterization of a mutant liver aldolase in adult hereditary fructose intolerance. Identification of the enzyme variant by radioassay in tissue biopsy specimens. | Cox TM | The Journal of clinical investigation | 1983 | PMID: 6348085 |
http://www.ctgt.net/disorder/smith-mccort-dysplasia-smc | - | - | - | - |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALDOB | - | - | - | - |
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Text-mined citations for rs1800546 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.