rs118204429
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000035.4(ALDOB):c.178C>T(p.Arg60Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000184 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R60R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000035.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDOB | NM_000035.4 | c.178C>T | p.Arg60Ter | stop_gained | 3/9 | ENST00000647789.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDOB | ENST00000647789.2 | c.178C>T | p.Arg60Ter | stop_gained | 3/9 | NM_000035.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152062Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251332Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135828
GnomAD4 exome AF: 0.000190 AC: 278AN: 1461888Hom.: 1 Cov.: 32 AF XY: 0.000177 AC XY: 129AN XY: 727244
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74390
ClinVar
Submissions by phenotype
Hereditary fructosuria Pathogenic:10Other:1
Likely pathogenic, no assertion criteria provided | literature only | ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul | Mar 18, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 26, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 09, 2017 | Variant summary: The ALDOB c.178C>T (p.Arg60X) variant results in a premature termination codon, predicted to cause a truncated or absent ALDOB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 20/277036 control chromosomes (gnomAD) at a frequency of 0.0000722, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALDOB variant (0.0044721). Multiple publications have cited the variant in affected compound heterozygote and homozygote patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 10, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
not provided, no classification provided | literature only | GeneReviews | - | One of the six most common HFI variants in US and European populations including Turkey, Spain, Central Europe, France, US, and Italy - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 08, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1994 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change creates a premature translational stop signal (p.Arg60*) in the ALDOB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDOB are known to be pathogenic (PMID: 18541450). This variant is present in population databases (rs118204429, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with hereditary fructose intolerance (PMID: 8071980, 8299883, 15880727, 20882353, 26937407). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 472). For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 21, 2022 | The c.178C>T (p.R60*) alteration, located in exon 3 (coding exon 2) of the ALDOB gene, consists of a C to T substitution at nucleotide position 178. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 60. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.0085% (24/282704) total alleles studied. The highest observed frequency was 0.01% (4/35438) of Latino alleles. This alteration has been reported in multiple patients with hereditary fructose intolerance (Brooks, 1994; Santer, 2005; Davit-Spraul, 2008; Valadares, 2015; Kim, 2021). Based on the available evidence, this alteration is classified as pathogenic. - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | May 09, 2019 | ACMG classification criteria: PVS1, PM2, PM3, PP3, PP5 - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 06, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also reported as R59X due to alternate nomenclature; This variant is associated with the following publications: (PMID: 25525159, 8299883, 8071980, 26937407, 15880727, 27604308, 20882353, 20033295, 8299892, 35398868, 18541450) - |
ALDOB-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 16, 2023 | The ALDOB c.178C>T variant is predicted to result in premature protein termination (p.Arg60*). This variant has been reported to be causative for hereditary fructose intolerance (Brooks et al. 1994. PubMed ID: 8299883; Valadares et al. 2015. PubMed ID: 26937407; Reid et al. 2016. PubMed ID: 27604308; Kim et al. 2021. PubMed ID: 33028743). Note, this is also referred to as R59op, Arg59Ter, and Arg60Ter in some literature. This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-104192183-G-A). Nonsense variants in ALDOB are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at