Submissions for variant NM_000035.4(ALDOB):c.686T>C (p.Leu229Pro)

dbSNP: rs1554702433

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665845	SCV000790031	uncertain significance	Hereditary fructosuria	2017-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665845	SCV002819756	likely pathogenic	Hereditary fructosuria	2022-12-23	criteria provided, single submitter	clinical testing	Variant summary: ALDOB c.686T>C (p.Leu229Pro) results in a non-conservative amino acid change affecting a highly conserved residue located in the Fructose-bisphosphate aldolase class-I active site (IPR029768) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251388 control chromosomes (gnomAD). c.686T>C has been reported in the literature in at least one compound heterozygous individual, who carried a pathogenic variant in trans, and was affected with Hereditary Fructose Intolerance (Esposito_2004, Di Dato_2019). These data indicate that the variant may be associated with disease. One of these publications also reported experimental evidence evaluating an impact on protein function, demonstrating that the recombinant protein expressed in E. coli is insoluble, indicating that the variant affects proper folding (Esposito_2004). Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	RCV000665845	SCV001573848	pathogenic	Hereditary fructosuria	2021-03-18	no assertion criteria provided	literature only