rs118204429

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000035.4(ALDOB):c.178C>T(p.Arg60*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000184 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R60R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

ALDOB
NM_000035.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 6.85

Publications

16 publications found

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 Gene-Disease associations (from GenCC):

hereditary fructose intolerance
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
complex neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ALDOB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 9-101429901-G-A is Pathogenic according to our data. Variant chr9-101429901-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDOB	NM_000035.4 link	c.178C>T	p.Arg60*	stop_gained	Exon 3 of 9	ENST00000647789.2	NP_000026.2	P05062A0A024R145

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDOB	ENST00000647789.2 link	c.178C>T	p.Arg60*	stop_gained	Exon 3 of 9		NM_000035.4	ENSP00000497767.1		P05062

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000836

AC:

AN:

251332

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000190

AC:

278

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

129

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000219

AC:

243

AN:

1112006

Other (OTH)

AF:

0.000248

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41508

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary fructosuria

Pathogenic:10Other:1

Mar 18, 2021

ATS em Genética Clínica, Universidade Federal do Rio Grande do Sul

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 26, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

One of the six most common HFI variants in US and European populations including Turkey, Spain, Central Europe, France, US, and Italy -

Mar 24, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Jun 10, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Nov 09, 2017

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

Inborn genetic diseases

Pathogenic:1

Apr 21, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. -

See cases

Pathogenic:1

May 09, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PVS1, PM2, PM3, PP3, PP5 -

not provided

Pathogenic:1

Sep 06, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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) -

ALDOB-related disorder

Pathogenic:1

Jun 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method: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. Nonsense variants in ALDOB are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

PhyloP100

6.8

Vest4

0.84

GERP RS

5.0

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over