chr5-126595191-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP2BP4

The NM_001182.5(ALDH7A1):c.8G>A(p.Arg3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,551,936 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

ALDH7A1
NM_001182.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.987

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 0.36846 (below the threshold of 3.09). Trascript score misZ: 0.93117 (below the threshold of 3.09). GenCC associations: The gene is linked to pyridoxine-dependent epilepsy, pyridoxine-dependent epilepsy caused by ALDH7A1 mutant.

BP4

Computational evidence support a benign effect (MetaRNN=0.31465656).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001182.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALDH7A1	NM_001182.5	MANE Select	c.8G>A	p.Arg3His	missense	Exon 1 of 18	NP_001173.2
ALDH7A1	NM_001202404.2		c.8G>A	p.Arg3His	missense	Exon 1 of 16	NP_001189333.2
ALDH7A1	NM_001201377.2		c.-77G>A		5_prime_UTR	Exon 1 of 18	NP_001188306.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALDH7A1	ENST00000409134.8	TSL:1 MANE Select	c.8G>A	p.Arg3His	missense	Exon 1 of 18	ENSP00000387123.3
ALDH7A1	ENST00000636879.1	TSL:5	c.8G>A	p.Arg3His	missense	Exon 1 of 19	ENSP00000490811.1
ALDH7A1	ENST00000635851.1	TSL:5	c.5G>A	p.Arg2His	missense	Exon 1 of 18	ENSP00000490819.1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000103

AC:

AN:

155706

AF XY:

0.000146

show subpopulations

Gnomad AFR exome

AF:

0.000124

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:

0.000199

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000328

AC:

459

AN:

1399738

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

240

AN XY:

690432

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31606

American (AMR)

AF:

0.0000280

AC:

AN:

35742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25190

East Asian (EAS)

AF:

0.00

AC:

AN:

35746

South Asian (SAS)

AF:

0.000126

AC:

AN:

79306

European-Finnish (FIN)

AF:

0.0000203

AC:

AN:

49328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000411

AC:

443

AN:

1079100

Other (OTH)

AF:

0.0000517

AC:

AN:

58022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

106

132

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:

0.000197

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.000154

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000118

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyridoxine-dependent epilepsy

Uncertain:3

Oct 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3 of the ALDH7A1 protein (p.Arg3His). This variant is present in population databases (rs759866910, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ALDH7A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 204866). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

Mar 16, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Apr 11, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:2

Jun 09, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_moderate

Oct 28, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis suggests that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

not specified

Uncertain:1

Mar 26, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ALDH7A1 c.8G>A (p.Arg3His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 155706 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ALDH7A1 causing Pyridoxine-Dependent Epilepsy (0.0001 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.8G>A in individuals affected with Pyridoxine-Dependent Epilepsy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 204866). Based on the evidence outlined above, the variant was classified as uncertain significance.

Inborn genetic diseases

Uncertain:1

May 02, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8G>A (p.R3H) alteration is located in exon 1 (coding exon 1) of the ALDH7A1 gene. This alteration results from a G to A substitution at nucleotide position 8, causing the arginine (R) at amino acid position 3 to be replaced by a histidine (H). The p.R3H alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.016

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.78

M_CAP

Benign

0.080

MetaRNN

Benign

0.22

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.7

PhyloP100

0.99

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.53

REVEL

Uncertain

0.39

Sift

Uncertain

0.0040

Sift4G

Benign

0.11

Polyphen

0.80

Vest4

0.30

MVP

0.92

MPC

0.19

ClinPred

0.079

GERP RS

3.5

PromoterAI

-0.27

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.075

gMVP

0.60

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over