9-101424931-C-T

Position:

chr9-101424931-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_000035.4(ALDOB):c.911G>A(p.Arg304Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R304W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

ALDOB
NM_000035.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:10

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

ALDOB (HGNC:417): (aldolase, fructose-bisphosphate B) Fructose-1,6-bisphosphate aldolase (EC 4.1.2.13) is a tetrameric glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Vertebrates have 3 aldolase isozymes which are distinguished by their electrophoretic and catalytic properties. Differences indicate that aldolases A, B, and C are distinct proteins, the products of a family of related 'housekeeping' genes exhibiting developmentally regulated expression of the different isozymes. The developing embryo produces aldolase A, which is produced in even greater amounts in adult muscle where it can be as much as 5% of total cellular protein. In adult liver, kidney and intestine, aldolase A expression is repressed and aldolase B is produced. In brain and other nervous tissue, aldolase A and C are expressed about equally. There is a high degree of homology between aldolase A and C. Defects in ALDOB cause hereditary fructose intolerance. [provided by RefSeq, Dec 2008]

ALDOB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDOB	NM_000035.4 linkuse as main transcript	c.911G>A	p.Arg304Gln	missense_variant	8/9	ENST00000647789.2	NP_000026.2	P05062A0A024R145

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDOB	ENST00000647789.2 linkuse as main transcript	c.911G>A	p.Arg304Gln	missense_variant	8/9	NM_000035.4	ENSP00000497767.1	P05062
ALDOB	ENST00000648064.1 linkuse as main transcript	c.911G>A	p.Arg304Gln	missense_variant	8/9		ENSP00000497990.1	P05062
ALDOB	ENST00000648758.1 linkuse as main transcript	c.911G>A	p.Arg304Gln	missense_variant	8/9		ENSP00000497731.1	P05062
ALDOB	ENST00000649902.1 linkuse as main transcript	c.911G>A	p.Arg304Gln	missense_variant	7/7		ENSP00000497216.1	A0A3B3IS80

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000215

AC:

AN:

251216

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000326

AC:

476

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000401

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000138

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary fructosuria

Pathogenic:3Uncertain:5

Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jan 31, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 02, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 27, 2022	- -
Likely pathogenic, no assertion criteria provided	literature only	ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul	Mar 18, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 01, 2021	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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 17, 2023	PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2024	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) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 05, 2022

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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

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. -

ALDOB-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2024

The ALDOB c.911G>A variant is predicted to result in the amino acid substitution p.Arg304Gln. This variant is also referred to as R303Q in the literature. This variant was reported in the heterozygous state in an individual with hereditary fructose intolerance ((Santamaria et al. 2000. PubMed ID: 10970798). In that patient, this variant was inherited from the patient’s presumably unaffected mother. Additional functional studies showed that this variant impacts ALDOB protein function (Santamaria et al. 2000. PubMed ID: 10970798). Of note, another variant impacting the same amino acid was reported in the homozygous state in an individual with hereditary fructose intolerance (Santamaria et al. 1996. PubMed ID: 8880583). This variant is reported in 0.037% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;D;D;D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;.;.;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.81

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;H;H;H;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.9

D;.;.;.;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.016

D;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;.;.

Polyphen

0.99

D;D;D;D;.

Vest4

0.98

MVP

0.95

MPC

0.13

ClinPred

0.75

GERP RS

4.8

Varity_R

0.83

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over