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

dbSNP: rs78340951

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723841	SCV000232899	pathogenic	not provided	2018-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000498	SCV000944145	pathogenic	Hereditary fructosuria	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 335 of the ALDOB protein (p.Asn335Lys). This variant is present in population databases (rs78340951, gnomAD 0.02%). This missense change has been observed in individuals with fructose intolerance (PMID: 1856829, 2336380, 12205126, 15880727, 18541450, 19768653, 23430936). This variant is also known as p.Asn334Lys. ClinVar contains an entry for this variant (Variation ID: 469). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ALDOB function (PMID: 12417303). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000000498	SCV001194035	pathogenic	Hereditary fructosuria	2019-12-19	criteria provided, single submitter	clinical testing	NM_000035.3(ALDOB):c.1005C>G(N335K) is classified as pathogenic in the context of hereditary fructose intolerance. Sources cited for classification include the following: PMID 2336380, 15880727, 20033295, and 8541450. Classification of NM_000035.3(ALDOB):c.1005C>G(N335K) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000000498	SCV001366458	pathogenic	Hereditary fructosuria	2019-03-12	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3.
Mendelics	RCV000000498	SCV002517551	pathogenic	Hereditary fructosuria	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000000498	SCV002767903	pathogenic	Hereditary fructosuria	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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 asparagine to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (34 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycolytic domain (PDB, NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic and pathogenic, and has been observed in many homozygous and compound heterozygous patients with hereditary fructose intolerance (ClinVar, PMID: 30833214, PMID: 15880727). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrate that this missense variant results in reduced catalytic activity and efficiency of substrates fructose-1,6-bisphosphate and fructose-1-phosphate (PMID: 12417303). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000723841	SCV002821959	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	ALDOB: PS3, PS4, PP1:Moderate
Revvity Omics, Revvity	RCV000000498	SCV003814945	pathogenic	Hereditary fructosuria	2022-12-15	criteria provided, single submitter	clinical testing
3billion	RCV000000498	SCV003841608	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: 0.012%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.48). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000469). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 12205126, 15880727, 18541450, 19768653, 23430936). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000000498	SCV004014026	pathogenic	Hereditary fructosuria	2023-05-02	criteria provided, single submitter	clinical testing	PM2, PP3, PP4, PP5
GeneDx	RCV000723841	SCV004040167	pathogenic	not provided	2024-06-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on the helical secondary structure and functional integrity (PMID: 12417303); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10024431, 12205126, 15532022, 20033295, 11757579, 15880727, 20848650, 23430936, 19768653, 18188031, 29368648, 1856829, 18541450, 34426522, 31589614, 22975760, 34162028, 2336380, 36384942, 12417303)
Baylor Genetics	RCV000000498	SCV004196104	pathogenic	Hereditary fructosuria	2024-03-29	criteria provided, single submitter	clinical testing
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
GeneReviews	RCV000000498	SCV000257574	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
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000723841	SCV001553838	pathogenic	not provided		no assertion criteria provided	clinical testing	The ALDOB p.N335K variant was identified in > 15 individuals with hereditary fructose intolerance as a homozygous or compound heterozygous variant (Santer_2005_PMID:15880727; Esposito_2010_PMID:20848650; Davit-Spraul_2008_PMID:18541450; Ferri_2012_PMID:23430936; Sánchez-Gutiérrez_2002_PMID:12417303; Sebastio_1991_PMID:1856829; Coffee_2010_PMID:20882353; Coffee_2010_PMID:20033295). The variant was identified in dbSNP (ID: rs78340951) and ClinVar (classified as pathogenic by Counsyl, EGL Genetic Diagnostics and three other submitters, and as likely pathogenic by Invitae). The variant was identified in control databases in 34 of 280458 chromosomes at a frequency of 0.0001212 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 31 of 127538 chromosomes (freq: 0.000243) and Latino in 3 of 35264 chromosomes (freq: 0.000085), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.N335 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.N335K variant was found to result in significantly reduced enzyme activity (Esposito_2002_PMID:12417303). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	RCV000000498	SCV001573856	pathogenic	Hereditary fructosuria	2021-03-18	no assertion criteria provided	literature only
Natera, Inc.	RCV000000498	SCV002078708	pathogenic	Hereditary fructosuria	2020-01-07	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398398	SCV004105841	pathogenic	ALDOB-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The ALDOB c.1005C>G variant is predicted to result in the amino acid substitution p.Asn335Lys. This variant (sometimes referred to as N334K in the literature) is commonly reported to be causative for hereditary fructose intolerance (Cross et al. 1990. PubMed ID 2336380; Santer et al. 2005. PubMed ID 15880727; Davit-Spraul et al. 2008. PubMed ID 18541450). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.