rs41281039
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000035.4(ALDOB):c.136A>T(p.Arg46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000035.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDOB | NM_000035.4 | c.136A>T | p.Arg46Trp | missense_variant | 3/9 | ENST00000647789.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDOB | ENST00000647789.2 | c.136A>T | p.Arg46Trp | missense_variant | 3/9 | NM_000035.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152162Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251192Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135768
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727230
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74454
ClinVar
Submissions by phenotype
Hereditary fructosuria Pathogenic:2Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 11, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2010 | - - |
Likely pathogenic, no assertion criteria provided | literature only | ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul | Mar 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the ALDOB protein (p.Arg46Trp). This variant is present in population databases (rs41281039, gnomAD 0.009%). This missense change has been observed in individual(s) with fructose intolerance (PMID: 20848650). ClinVar contains an entry for this variant (Variation ID: 30979). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ALDOB function (PMID: 20848650). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2017 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2021 | Variant summary: ALDOB c.136A>T (p.Arg46Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251192 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALDOB causing Hereditary Fructose Intolerance (4.4e-05 vs 0.0045), allowing no conclusion about variant significance. c.136A>T has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual affected with Hereditary Fructose Intolerance who was reported as having mild hypoglycemia and ketosis after ingestion of fructose, and a marked aversion to sweets and fruit (example, Espositio_2021). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Esposito_2021). The most pronounced variant effect results in impaired catalysis towards Fructose-1-Phosphate (F1P) without producing any functional alteration in Fructose 1,6-biphosphate (FBP) metabolism. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=2; Likely Pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 04, 2017 | - - |
ALDOB-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 21, 2023 | The ALDOB c.136A>T variant is predicted to result in the amino acid substitution p.Arg46Trp. This variant was reported in the heterozygous state in an individual with suspected fructose intolerance; however, no additional potential causative variant was identified in this individual (Esposito et al. 2010. PubMed ID: 20848650). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-104192225-T-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at