5-126568296-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The NM_001182.5(ALDH7A1):c.834G>A(p.Val278Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V278V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

ALDH7A1
NM_001182.5 synonymous

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 1.32

Publications

15 publications found

Variant links:

Genes affected

ALDH7A1 (HGNC:877): (aldehyde dehydrogenase 7 family member A1) The protein encoded by this gene is a member of subfamily 7 in the aldehyde dehydrogenase gene family. These enzymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This particular member has homology to a previously described protein from the green garden pea, the 26g pea turgor protein. It is also involved in lysine catabolism that is known to occur in the mitochondrial matrix. Recent reports show that this protein is found both in the cytosol and the mitochondria, and the two forms likely arise from the use of alternative translation initiation sites. An additional variant encoding a different isoform has also been found for this gene. Mutations in this gene are associated with pyridoxine-dependent epilepsy. Several related pseudogenes have also been identified. [provided by RefSeq, Jan 2011]

ALDH7A1 Gene-Disease associations (from GenCC):

pyridoxine-dependent epilepsy
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet, ClinGen
pyridoxine-dependent epilepsy caused by ALDH7A1 mutant
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ALDH7A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 5-126568296-C-T is Pathogenic according to our data. Variant chr5-126568296-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 18002.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
ALDH7A1	NM_001182.5 link	c.834G>A	p.Val278Val	synonymous_variant	Exon 9 of 18	ENST00000409134.8	NP_001173.2	P49419-1
ALDH7A1	NM_001201377.2 link	c.750G>A	p.Val250Val	synonymous_variant	Exon 9 of 18		NP_001188306.1	P49419-2
ALDH7A1	NM_001202404.2 link	c.834G>A	p.Val278Val	synonymous_variant	Exon 9 of 16		NP_001189333.2	P49419-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8 link	c.834G>A	p.Val278Val	synonymous_variant	Exon 9 of 18	1	NM_001182.5	ENSP00000387123.3		P49419-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000557

AC:

AN:

251486

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000198

AC:

289

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000256

AC:

285

AN:

1111990

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000395

Hom.:

Bravo

AF:

0.0000491

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyridoxine-dependent epilepsy

Pathogenic:5Other:1

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 278 of the ALDH7A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ALDH7A1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs201948406, gnomAD 0.01%). This variant has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 17721876, 19128417, 20554659, 20814824, 22529283, 23022070, 23430810, 24122892, 27438048). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.750G>A. ClinVar contains an entry for this variant (Variation ID: 18002). Studies have shown that this variant results in cryptic splice site activation, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 17721876). For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 08, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ALDH7A1 c.834G>A alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Salomons_2007). The variant allele was found at a frequency of 5.6e-05 in 251486 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ALDH7A1 causing Pyridoxine-Dependent Epilepsy (5.6e-05 vs 0.0018), allowing no conclusion about variant significance. c.834G>A (also known as c.750G>A. ) has been reported in the literature in multiple individuals affected with Pyridoxine-Dependent Epilepsy (examples: Salomons_2007 and Marguet_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17721876, 27438048). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

The 2nd most common pathogenic variant, accounting for 5.4% of pathogenic variants -

not provided

Pathogenic:2

Feb 24, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect, suggesting this variant leads to abnormal gene splicing (PMID: 17721876); This variant is associated with the following publications: (PMID: 23022070, 22529283, 20554659, 36065636, 19128417, 24122892, 17721876, 26026794, 27324284, 23430810, 28973083, 29852413, 24748525, 20814824, 30043187, 31589614, 35782612, 31440721, 27438048) -

Dec 27, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jan 31, 2018

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.834G>A variant (also known as p.V278V), located in coding exon 9, results from a G to A substitution at nucleotide position 834 of the ALDH7A1 gene. This nucleotide substitution does not change the amino acid at codon 278. This nucleotide position is well conserved in available vertebrate species. This alteration has been detected in the homozygous and compound heterozygous state with other ALDH7A1 variants in several individuals with diagnoses of pyridoxine-dependent epilepsy (PDE) (Salomons GS et al. Ann. Neurol., 2007 Oct;62:414-8; Mercimek-Mahmutoglu S et al. Pediatrics, 2012 May;129:e1368-72; Proudfoot M et al. JIMD Rep, 2013 Mar;10:103-6; Coughlin CR et al. Mol. Genet. Metab. May;116:35-43; Yuzyuk T et al. Mol. Genet. Metab., 2016 07;118:167-72). In one study, authors isolated RNA from a homozygous individual to show that this alteration preferentially uses a cryptic donor splice site resulting in an out of frame deletion in exon 9 which leads to the p.Val250Glyfs*23 frameshift (Salomons GS et al. Ann. Neurol., 2007 Oct;62:414-8). Of note, this alteration is often called p.V250V (c.750G>A) in the literature. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to create a new alternate splice donor site, but BDGP does not predict the creation of a non-native donor site, nor a deleterious effect on splicing; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

ALDH7A1-related disorder

Pathogenic:1

Jul 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ALDH7A1 c.834G>A variant is not predicted to result in an amino acid change (p.=). This variant can also be denoted as c.750G>A (p.Val250Val) using transcript NM_001201377. This variant has been commonly reported in the homozygous and compound heterozygous states in patients with pyridoxine-dependent epilepsy (e.g., Salomons et al. 2007. PubMed ID: 17721876; Bennett et al. 2009. PubMed ID: 19128417; Mills et al. 2010. PubMed ID: 20554659; Mercimek-Mahmutoglu et al. 2012. PubMed ID: 22529283). Splicing prediction programs indicate that the c.834G>A variant strengthens a cryptic splice donor site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). RNA studies from a homozygous patient and her relatives confirmed the activation of the cryptic splice site, which was found to lead to a deletion of 40 nucleotides in the ALDH7A1 mRNA and was predicted to lead to a frameshift and premature protein termination; the results of their studies indicated that this change may also lead to nonsense-mediated mRNA decay (Salomons et al. 2007. PubMed ID: 17721876). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Seizure

Pathogenic:1

Mar 01, 2024

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.70

Position offset: 3

DS_DL_spliceai

0.59

Position offset: -37

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