ClinVar Miner

Submissions for variant NM_000035.4(ALDOB):c.324+8C>G (rs118168553)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000176966 SCV000228759 benign not specified 2015-02-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000320539 SCV000476068 likely benign Hereditary fructosuria 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000176966 SCV000718448 benign not specified 2017-06-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000176966 SCV000918414 benign not specified 2018-11-01 criteria provided, single submitter clinical testing Variant summary: ALDOB c.324+8C>G alters a non-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 no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0029 in 275448 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.035 in the gnomAD database, including 17 homozygotes. The observed variant frequency within East Asian control individuals is approximately 7.8-fold above the estimated maximal expected allele frequency for a pathogenic variant in ALDOB causing Hereditary Fructose Intolerance phenotype (0.0045), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.324+8C>G in individuals affected with Hereditary Fructose Intolerance and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

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