Submissions for variant NM_000035.4(ALDOB):c.911G>A (p.Arg304Gln)

gnomAD frequency: 0.00013  dbSNP: rs145078268

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000477962	SCV001330367	uncertain significance	Hereditary fructosuria	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001567261	SCV001790913	uncertain significance	not provided	2024-07-02	criteria provided, single submitter	clinical testing	Identified as a single heterozygous variant in an individual with hereditary fructose intolerance; reported as R303Q due to alternate nomenclature (PMID: 10970798); Published functional studies demonstrate impaired enzyme activity (PMID: 10970798); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 22995991, 21228398, 31589614, 37743645, 34524712, 20848650, 35460079, 36028839, 36890159, 10970798)
Myriad Genetics, Inc.	RCV000477962	SCV002060073	uncertain significance	Hereditary fructosuria	2021-11-01	criteria provided, single submitter	clinical testing	NM_000035.3(ALDOB):c.911G>A(R304Q) is a missense variant classified as a variant of uncertain significance in the context of hereditary fructose intolerance. R304Q has been observed in a case with relevant disease (PMID: 10970798). Functional assessments of this variant are available in the literature (PMID: 10970798). R304Q has been observed in population frequency databases (gnomAD: AMR 0.04%). In summary, there is insufficient evidence to classify NM_000035.3(ALDOB):c.911G>A(R304Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222519	SCV002500112	uncertain significance	not specified	2022-03-05	criteria provided, single submitter	clinical testing	Variant summary: ALDOB c.911G>A (p.Arg304Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251216 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALDOB causing Hereditary Fructose Intolerance (0.00021 vs 0.0045), allowing no conclusion about variant significance. c.911G>A has been reported in the literature without a second allele detected in at-least one individual affected with Hereditary Fructose Intolerance (example, Santamaria_2000). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Fructose Intolerance. At least one publication reports experimental evidence evaluating an impact on protein function (example, Santamaria_2000). The most pronounced variant effect results in impaired but not abolished catalytic efficiency in-vitro towards Fructose 1,6-bisphosphate and Fructose 1-phosphate as substrates as evidenced by decreased specific activity, increased Km, decreased Kcat and increased Kcat/Km. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000477962	SCV002766669	likely pathogenic	Hereditary fructosuria	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hereditary fructose intolerance (MIM#229600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (58 heterozygotes, 0 homozygotes). (SP) 0309 - Two alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a minor amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as VUS and likely pathogenic in ClinVar. It has also been reported in a heterozygous individual with hereditary fructose intolerance (PMID: 10970798). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrated reduced catalytic efficiency of the protein (PMID: 10970798). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change to a tryptophan has been reported in a homozygous individual with hereditary fructose intolerance (PMID: 8880583). It was subsequently shown to impair normal enzyme activities (PMID: 10970798). It has also been reported as VUS and pathogenic in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000477962	SCV002788231	uncertain significance	Hereditary fructosuria	2022-04-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477962	SCV003274571	uncertain significance	Hereditary fructosuria	2022-07-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 304 of the ALDOB protein (p.Arg304Gln). This variant is present in population databases (rs145078268, gnomAD 0.04%). This missense change has been observed in individual(s) with hereditary fructose intolerance (PMID: 10970798). This variant is also known as p.Arg303Gln. ClinVar contains an entry for this variant (Variation ID: 417929). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ALDOB function (PMID: 10970798). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002526509	SCV003538099	uncertain significance	Inborn genetic diseases	2022-07-08	criteria provided, single submitter	clinical testing	The c.911G>A (p.R304Q) alteration is located in exon 8 (coding exon 7) of the ALDOB gene. This alteration results from a G to A substitution at nucleotide position 911, causing the arginine (R) at amino acid position 304 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV001567261	SCV004225064	uncertain significance	not provided	2023-04-17	criteria provided, single submitter	clinical testing	PP3
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477962	SCV000536871	likely pathogenic	Hereditary fructosuria	2016-01-31	no assertion criteria provided	research
ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	RCV000477962	SCV001573854	likely pathogenic	Hereditary fructosuria	2021-03-18	no assertion criteria provided	literature only
Natera, Inc.	RCV000477962	SCV002078709	uncertain significance	Hereditary fructosuria	2020-01-19	no assertion criteria provided	clinical testing