ClinVar Miner

Submissions for variant NM_000035.4(ALDOB):c.324G>A (p.Lys108=) (rs750026492)

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Total submissions: 4
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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 2019-08-28 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. This variant also falls at the last nucleotide of exon 3 of the ALDOB coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs750026492, ExAC 0.009%). This variant has been observed in combination with another ALDOB variant in individuals affected with hereditary fructose intolerance (PMID: 12205126, 18541450, Invitae). ClinVar contains an entry for this variant (Variation ID: 188779). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (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.
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

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