ClinVar Genomic variation as it relates to human health
NM_000035.4(ALDOB):c.1013C>T (p.Ala338Val)
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
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NM_000035.4(ALDOB):c.1013C>T (p.Ala338Val)
Variation ID: 188739 Accession: VCV000188739.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q31.1 9: 101421891 (GRCh38) [ NCBI UCSC ] 9: 104184173 (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 Mar 29, 2015 Jun 17, 2024 Mar 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000035.4:c.1013C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000026.2:p.Ala338Val missense NC_000009.12:g.101421891G>A NC_000009.11:g.104184173G>A NG_012387.1:g.18890C>T LRG_1244:g.18890C>T LRG_1244t1:c.1013C>T LRG_1244p1:p.Ala338Val P05062:p.Ala338Val - Protein change
- A338V
- Other names
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- Canonical SPDI
- NC_000009.12:101421890:G:A
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00013
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
510 | 549 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (12) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2024 | RCV000169047.27 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 31, 2023 | RCV000598061.23 |
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
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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
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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 19, 2022)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002547848.1
First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
Variant summary: ALDOB c.1013C>T (p.Ala338Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ALDOB c.1013C>T (p.Ala338Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 249676 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALDOB causing Hereditary Fructose Intolerance (0.00015 vs 0.0045), allowing no conclusion about variant significance. c.1013C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Hereditary Fructose Intolerance (example, Rellos_1999, Gunduz_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Rellos_1999). The most pronounced variant effect results in preferentially decreased affinity and activity towards its specific F-1-P substrate. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Mar 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary fructosuria
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746895.3
First in ClinVar: Mar 29, 2015 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 2
Age: 10-19 years
Sex: male
Geographic origin: Iran
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Pathogenic
(Jul 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary fructosuria
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002804601.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Jul 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV004022763.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20848650, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20848650, 15532022, 20033295, 34426522, 32860008, 35314707, 32368696, 28991257, 8535439, 10024431, 31343797, 34162028, 8299892, 9610797, 18541450, 25595217) (less)
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Pathogenic
(Mar 29, 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: SCV004805769.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
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Likely pathogenic
(Feb 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334764.21
First in ClinVar: Jun 08, 2020 Last updated: Jun 17, 2024 |
Number of individuals with the variant: 3
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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:
unknown
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Baylor Genetics
Accession: SCV001163584.2
First in ClinVar: Feb 29, 2020 Last updated: Jun 17, 2024 |
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Pathogenic
(May 08, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000708361.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hereditary fructosuria
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV001426597.1
First in ClinVar: Aug 08, 2020 Last updated: Aug 08, 2020 |
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Likely pathogenic
(Mar 28, 2014)
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criteria provided, single submitter
Method: literature only
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Hereditary fructosuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220205.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Jan 31, 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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Invitae
Accession: SCV000933103.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 338 of the ALDOB protein (p.Ala338Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 338 of the ALDOB protein (p.Ala338Val). This variant is present in population databases (rs77718928, gnomAD 0.06%). This missense change has been observed in individual(s) with hereditary fructose intolerance (PMID: 9610797, 25595217). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as A337V. ClinVar contains an entry for this variant (Variation ID: 188739). 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: 10229688). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 02, 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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848892.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Ala338Val variant in ALDOB has been reported in at least 5 homozygous and 5 compound heterozygous individuals with hereditary fructose intolerance and segregated with … (more)
The p.Ala338Val variant in ALDOB has been reported in at least 5 homozygous and 5 compound heterozygous individuals with hereditary fructose intolerance and segregated with disease in 2 affected individuals from 1 family (Rellos 1999 PMID: 10229688, Davit-Spraul 2008 PMID: 18541450, Coffee 2010 PMID: 20033295, Bijarnia-Mahay 2015 PMID: 25595217). It has also been identified in 0.6% (2/316) Middle Eastern and 0.03% (13/41434) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 188739). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant decreases binding affinity of the protein and results in a partially denatured protein (Rellos 1999 PMID: 10229688). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hereditary fructose intolerance. ACMG/AMP Criteria applied: PM3_Strong, PP1_Moderate, PP3, PS3_Supporting. (less)
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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: SCV001573857.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
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Likely pathogenic
(May 25, 2021)
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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: SCV002078706.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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: SCV002029087.2
First in ClinVar: Dec 04, 2021 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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Molecular and clinical findings of Turkish patients with hereditary fructose intolerance. | Gunduz M | Journal of pediatric endocrinology & metabolism : JPEM | 2021 | PMID: 34162028 |
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
Molecular Diagnosis of Hereditary Fructose Intolerance: Founder Mutation in a Community from India. | Bijarnia-Mahay S | JIMD reports | 2015 | PMID: 25595217 |
Integration of PCR-Sequencing Analysis with Multiplex Ligation-Dependent Probe Amplification for Diagnosis of Hereditary Fructose Intolerance. | Ferri L | JIMD reports | 2012 | PMID: 23430936 |
Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion. | Esposito G | Human mutation | 2010 | PMID: 20848650 |
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 |
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 |
The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. | Santer R | Human mutation | 2005 | PMID: 15880727 |
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 |
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 |
Alteration of substrate specificity by a naturally-occurring aldolase B mutation (Ala337-->Val) in fructose intolerance. | Rellos P | The Biochemical journal | 1999 | PMID: 10229688 |
Screening for hereditary fructose intolerance mutations by reverse dot-blot. | Lau J | Molecular and cellular probes | 1999 | PMID: 10024431 |
Hereditary fructose intolerance. | Ali M | Journal of medical genetics | 1998 | PMID: 9610797 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALDOB | - | - | - | - |
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Text-mined citations for rs77718928 ...
HelpRecord last updated Jun 23, 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.