Submissions for variant NM_000035.4(ALDOB):c.770T>C (p.Leu257Pro)

dbSNP: rs764701775

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001376709	SCV004029605	pathogenic	Hereditary fructosuria	2023-07-13	criteria provided, single submitter	clinical testing	Variant summary: ALDOB c.770T>C (p.Leu257Pro) 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 4e-06 in 251444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.770T>C has been reported in the literature in multiple compound heterozygous individuals affected with Hereditary Fructose Intolerance (e.g., Ali_1994, Ciacci_2006, Coffee_2010, Stormon_2004). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in reduced protein stability, a moderate reduction in specific activity (16-38% depending on the substrate), and an approximately 70% reduction in catalytic efficiency with the FBP substrate relative to the wild type (e.g., Esposito_2002). The following publications have been ascertained in the context of this evaluation (PMID: 8069328, 16630753, 20882353, 12417303, 14760272). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001376709	SCV004296043	pathogenic	Hereditary fructosuria	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 257 of the ALDOB protein (p.Leu257Pro). This variant is present in population databases (rs764701775, gnomAD 0.002%). This missense change has been observed in individual(s) with fructose intolerance (PMID: 8162030, 14760272, 20033295). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Leu256->Pro. ClinVar contains an entry for this variant (Variation ID: 1065855). 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: 10625657, 12417303). For these reasons, this variant has been classified as Pathogenic.
ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	RCV001376709	SCV001573850	pathogenic	Hereditary fructosuria	2021-03-18	no assertion criteria provided	literature only