NM_001182.5:c.364C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM5PP2PP3_ModeratePP5

The NM_001182.5(ALDH7A1):c.364C>T(p.Arg122Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,614,028 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. R122Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

ALDH7A1
NM_001182.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 3.57

Publications

7 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 6 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-126583960-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 860878.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant 5-126583961-G-A is Pathogenic according to our data. Variant chr5-126583961-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204863.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH7A1	NM_001182.5 link	c.364C>T	p.Arg122Trp	missense_variant	Exon 4 of 18	ENST00000409134.8	NP_001173.2	P49419-1
ALDH7A1	NM_001201377.2 link	c.280C>T	p.Arg94Trp	missense_variant	Exon 4 of 18		NP_001188306.1	P49419-2
ALDH7A1	NM_001202404.2 link	c.364C>T	p.Arg122Trp	missense_variant	Exon 4 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.364C>T	p.Arg122Trp	missense_variant	Exon 4 of 18	1	NM_001182.5	ENSP00000387123.3		P49419-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000915

AC:

AN:

251474

AF XY:

0.0000883

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000657

AC:

AN:

1111936

Other (OTH)

AF:

0.0000828

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41538

American (AMR)

AF:

0.000327

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

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:

0.0000847

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pyridoxine-dependent epilepsy

Pathogenic:3

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 122 of the ALDH7A1 protein (p.Arg122Trp). This variant is present in population databases (rs370624118, gnomAD 0.03%). This missense change has been observed in individual(s) with pyridoxine-dependent epilepsy (internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 204863). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ALDH7A1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Oct 12, 2023

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ALDH7A1 c.364C>T (p.Arg122Trp) results in a non-conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251474 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALDH7A1 causing Pyridoxine-Dependent Epilepsy (9.1e-05 vs 0.0018), allowing no conclusion about variant significance. c.364C>T has been reported in the literature in individuals affected with Pyridoxine-Dependent Epilepsy, and was shown to segregate with disease in two affected brothers (example, Coughlin_2019, Jiao_2020, Jiao_2021, McKnight_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the enzyme activity of the variant to be 81% of wild type (Coughlin_2019). The following publications have been ascertained in the context of this evaluation (PMID: 25969726, 30043187, 31737911, 33868381, 34926809). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=1, VUS, n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

May 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jul 18, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R122W variant (also known as c.364C>T), located in coding exon 4 of the ALDH7A1 gene, results from a C to T substitution at nucleotide position 364. The arginine at codon 122 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the T allele has an overall frequency of 0.009% (26/282864) total alleles studied. The highest observed frequency was 0.031% (11/35440) of Latino alleles. This variant has been identified in conjunction with other ALDH7A1 variants in individuals with features consistent with autosomal recessive pyridoxine-dependent epilepsy; in at least one instance, the variants were identified in trans (Coughlin, 2019; Jiao, 2021). -

not provided

Pathogenic:1

Jul 17, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 30043187, 32956737, 33868381, 31737911, 34926809) -

not specified

Uncertain:1

Sep 28, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;D;T;.;.;.;.;T;T;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Pathogenic

4.2

.;H;.;.;.;.;H;.;.;.

PhyloP100

3.6

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.7

.;D;.;.;.;.;D;.;.;.

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

.;D;.;.;.;.;D;.;.;.

Sift4G

Pathogenic

0.0

.;D;.;.;.;.;D;.;D;.

Polyphen

1.0

.;D;.;.;.;.;.;.;.;.

Vest4

0.90, 0.89, 0.87

MVP

0.95

MPC

0.67

ClinPred

1.0

GERP RS

3.4

Varity_R

0.90

gMVP

0.78

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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