Submissions for variant NM_000035.4(ALDOB):c.113-1_115del

dbSNP: rs786204598

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169352	SCV000220722	likely pathogenic	Hereditary fructosuria	2014-09-23	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169352	SCV000918413	likely pathogenic	Hereditary fructosuria	2023-01-08	criteria provided, single submitter	clinical testing	Variant summary: ALDOB c.113-1_115delGGTA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250930 control chromosomes. c.113-1_115delGGTA has been reported in the literature as a homozygous or compound heterozygous genotype in at-least two individuals affected with Hereditary Fructose Intolerance and subsequently cited by others (example, Cross_1990, Ali_1998, Kaiser_1991). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000169352	SCV001163211	pathogenic	Hereditary fructosuria	2024-03-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169352	SCV001225800	pathogenic	Hereditary fructosuria	2024-02-23	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 3 (c.113-1_115del) of the ALDOB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALDOB are known to be pathogenic (PMID: 18541450). This variant is present in population databases (rs786204598, gnomAD 0.002%). This variant has been observed in individuals with fructose intolerance (PMID: 2349937, 15880727). ClinVar contains an entry for this variant (Variation ID: 188974). For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV000169352	SCV003841990	pathogenic	Hereditary fructosuria	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (PMID: 2349937). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000169352	SCV005679609	pathogenic	Hereditary fructosuria	2024-05-30	criteria provided, single submitter	clinical testing
GeneDx	RCV005235079	SCV005882000	pathogenic	not provided	2024-09-06	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, 32709737, 34162028, 15880727, 1772121, 2349937)
ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	RCV000169352	SCV001573863	likely pathogenic	Hereditary fructosuria	2021-03-18	no assertion criteria provided	literature only