Submissions for variant NM_000035.4(ALDOB):c.136A>T (p.Arg46Trp)

gnomAD frequency: 0.00001  dbSNP: rs41281039

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000023970	SCV000800621	uncertain significance	Hereditary fructosuria	2017-11-09	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000728543	SCV000856134	uncertain significance	not provided	2017-08-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804747	SCV002051071	uncertain significance	not specified	2021-12-13	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000023970	SCV002806864	uncertain significance	Hereditary fructosuria	2022-01-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000023970	SCV003441302	uncertain significance	Hereditary fructosuria	2022-08-22	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV003415737	SCV004106350	uncertain significance	ALDOB-related disorder	2023-06-21	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000023970	SCV000045261	pathogenic	Hereditary fructosuria	2010-12-01	no assertion criteria provided	literature only
ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	RCV000023970	SCV001573829	likely pathogenic	Hereditary fructosuria	2021-03-18	no assertion criteria provided	literature only