ClinVar Miner

Submissions for variant NM_000035.4(ALDOB):c.1005C>G (p.Asn335Lys) (rs78340951)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723841 SCV000232899 pathogenic not provided 2018-02-06 criteria provided, single submitter clinical testing
Counsyl RCV000000498 SCV000485178 pathogenic Hereditary fructosuria 2016-03-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000000498 SCV000916435 pathogenic Hereditary fructosuria 2017-11-20 criteria provided, single submitter clinical testing Variant summary: The ALDOB c.1005C>G (p.Asn335Lys) variant involves the alteration of a non-conserved nucleotide that 5/5 in silico tools predict to have a damaging outcome. This variant was found in 32/278824 control chromosomes at a frequency of 0.0001148, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALDOB variant (0.0044721). The variant has been identified in numerous HFI patients as both a compound heterozygous and homozygous allele (Coffee_2010; Santer_2005). In addition, a functional study showed that the variant enzyme activity and catalytic effiency were severely reduced compared to WT controls (Esposito_2002). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000000498 SCV000944145 likely pathogenic Hereditary fructosuria 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 335 of the ALDOB protein (p.Asn335Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs78340951, ExAC 0.02%). This variant has been observed as homozygous or in combination with another ALDOB variant in individuals affected with fructose intolerance (PMID: 19768653, 18541450, 15880727, 2336380, 23430936, 12205126, 1856829). This variant is also known as p.Asn334Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 469). Experimental studies have shown that this missense change causes a reduction in both ALDOB enzyme activity and affinity for the substrate (PMID: 12417303). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000000498 SCV000020647 pathogenic Hereditary fructosuria 2008-08-01 no assertion criteria provided literature only
HFI Laboratory at Boston University,Boston University RCV000000498 SCV000067377 pathogenic Hereditary fructosuria no assertion criteria provided clinical testing
DLE - Diagnosticos Laboratoriais Especializados RCV000000498 SCV000077517 pathogenic Hereditary fructosuria no assertion criteria provided clinical testing
GeneReviews RCV000000498 SCV000257574 pathogenic Hereditary fructosuria 2015-10-07 no assertion criteria provided literature only

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