Submissions for variant NM_000035.4(ALDOB):c.442T>C (p.Trp148Arg)

gnomAD frequency: 0.00004  dbSNP: rs118204430

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265544	SCV002547838	uncertain significance	not specified	2022-05-26	criteria provided, single submitter	clinical testing	Variant summary: ALDOB c.442T>C (p.Trp148Arg) 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 2.8e-05 in 251184 control chromosomes. c.442T>C has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Hereditary Fructose Intolerance (example, Ali_1995 cited in Pinheiro_2021). At least one publication reports experimental evidence evaluating an impact on protein function (example, Rellos_2000). The most pronounced variant effect results in 16-20% of normal aldolase enzyme activity in vitro. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical reports supported by published/peer consensus are obtained, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000504	SCV003259629	uncertain significance	Hereditary fructosuria	2022-07-08	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 148 of the ALDOB protein (p.Trp148Arg). This variant is present in population databases (rs118204430, gnomAD 0.007%). This missense change has been observed in individual(s) with ALDOB-related conditions (PMID: 7717389). ClinVar contains an entry for this variant (Variation ID: 475). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ALDOB function (PMID: 12417303). 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.
OMIM	RCV000000504	SCV000020653	pathogenic	Hereditary fructosuria	1995-04-01	no assertion criteria provided	literature only
ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	RCV000000504	SCV001573836	pathogenic	Hereditary fructosuria	2021-03-18	no assertion criteria provided	literature only