Submissions for variant NM_000035.4(ALDOB):c.178C>T (p.Arg60Ter)

gnomAD frequency: 0.00010  dbSNP: rs118204429

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000000501	SCV000220395	likely pathogenic	Hereditary fructosuria	2014-06-10	criteria provided, single submitter	literature only
GeneDx	RCV000760464	SCV000890352	pathogenic	not provided	2022-09-06	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also reported as R59X due to alternate nomenclature; This variant is associated with the following publications: (PMID: 25525159, 8299883, 8071980, 26937407, 15880727, 27604308, 20882353, 20033295, 8299892, 35398868, 18541450)
Fulgent Genetics, Fulgent Genetics	RCV000000501	SCV000894462	pathogenic	Hereditary fructosuria	2021-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000501	SCV000916436	pathogenic	Hereditary fructosuria	2017-11-09	criteria provided, single submitter	clinical testing	Variant summary: The ALDOB c.178C>T (p.Arg60X) variant results in a premature termination codon, predicted to cause a truncated or absent ALDOB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 20/277036 control chromosomes (gnomAD) at a frequency of 0.0000722, which does not exceed the estimated maximal expected allele frequency of a pathogenic ALDOB variant (0.0044721). Multiple publications have cited the variant in affected compound heterozygote and homozygote patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000000501	SCV000964566	pathogenic	Hereditary fructosuria	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg60*) in the ALDOB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDOB are known to be pathogenic (PMID: 18541450). This variant is present in population databases (rs118204429, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with hereditary fructose intolerance (PMID: 8071980, 8299883, 15880727, 20882353, 26937407). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 472). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000000501	SCV001810254	pathogenic	Hereditary fructosuria	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000000501	SCV002024916	pathogenic	Hereditary fructosuria	2022-01-26	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251843	SCV002523704	pathogenic	See cases	2019-05-09	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM2, PM3, PP3, PP5
Ambry Genetics	RCV002512606	SCV003528888	pathogenic	Inborn genetic diseases	2022-04-21	criteria provided, single submitter	clinical testing	The c.178C>T (p.R60*) alteration, located in exon 3 (coding exon 2) of the ALDOB gene, consists of a C to T substitution at nucleotide position 178. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 60. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.0085% (24/282704) total alleles studied. The highest observed frequency was 0.01% (4/35438) of Latino alleles. This alteration has been reported in multiple patients with hereditary fructose intolerance (Brooks, 1994; Santer, 2005; Davit-Spraul, 2008; Valadares, 2015; Kim, 2021). Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003407248	SCV004113432	pathogenic	ALDOB-related condition	2023-05-16	criteria provided, single submitter	clinical testing	The ALDOB c.178C>T variant is predicted to result in premature protein termination (p.Arg60*). This variant has been reported to be causative for hereditary fructose intolerance (Brooks et al. 1994. PubMed ID: 8299883; Valadares et al. 2015. PubMed ID: 26937407; Reid et al. 2016. PubMed ID: 27604308; Kim et al. 2021. PubMed ID: 33028743). Note, this is also referred to as R59op, Arg59Ter, and Arg60Ter in some literature. This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-104192183-G-A). Nonsense variants in ALDOB are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000000501	SCV004196071	pathogenic	Hereditary fructosuria	2023-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000000501	SCV000020650	pathogenic	Hereditary fructosuria	1994-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000000501	SCV000257568	not provided	Hereditary fructosuria		no assertion provided	literature only	One of the six most common HFI variants in US and European populations including Turkey, Spain, Central Europe, France, US, and Italy
Natera, Inc.	RCV000000501	SCV001462846	pathogenic	Hereditary fructosuria	2020-09-16	no assertion criteria provided	clinical testing
ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	RCV000000501	SCV001573831	likely pathogenic	Hereditary fructosuria	2021-03-18	no assertion criteria provided	literature only