Submissions for variant NM_000035.4(ALDOB):c.324G>A (p.Lys108=)

dbSNP: rs750026492

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169107	SCV000220307	likely pathogenic	Hereditary fructosuria	2014-05-13	criteria provided, single submitter	literature only
Invitae	RCV000169107	SCV001225333	pathogenic	Hereditary fructosuria	2023-09-18	criteria provided, single submitter	clinical testing	This sequence change affects codon 108 of the ALDOB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ALDOB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 4 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs750026492, gnomAD no frequency). This variant has been observed in individual(s) with clinical features of ALDOB-related conditions (PMID: 12205126, 18541450; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as g.1133G>A. ClinVar contains an entry for this variant (Variation ID: 188779). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 3 (PMID: 12205126). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169107	SCV001361107	likely pathogenic	Hereditary fructosuria	2019-10-14	criteria provided, single submitter	clinical testing	Variant summary: ALDOB c.324G>A (p.Lys108Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict that the variant has a significant impact on normal splicing by either abolishing or weakening a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Sanchez-Gutierrez_2002). The variant allele was found at a frequency of 4e-06 in 249854 control chromosomes (gnomAD). c.324G>A has been reported in the literature in individuals affected with Hereditary Fructose Intolerance (Sanchez-Gutierrez_2002, Davit-Spraul_2008). These data indicate that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000169107	SCV002781577	likely pathogenic	Hereditary fructosuria	2021-10-02	criteria provided, single submitter	clinical testing
ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	RCV000169107	SCV001573884	likely pathogenic	Hereditary fructosuria	2021-03-18	no assertion criteria provided	literature only