rs140845195

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong

The NM_001182.5(ALDH7A1):c.1566-1G>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000873 in 1,604,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

ALDH7A1
NM_001182.5 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.88

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 22 ACMG points.

PVS1

Splicing variant, LoF is a know mechanism of disease,

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 5-126545020-C-A is Pathogenic according to our data. Variant chr5-126545020-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 374140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126545020-C-A is described in Lovd as [Pathogenic]. Variant chr5-126545020-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
ALDH7A1	NM_001182.5 linkuse as main transcript	c.1566-1G>T	splice_acceptor_variant	ENST00000409134.8
ALDH7A1	NM_001201377.2 linkuse as main transcript	c.1482-1G>T	splice_acceptor_variant
ALDH7A1	NM_001202404.2 linkuse as main transcript	c.1374-1G>T	splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH7A1	ENST00000409134.8 linkuse as main transcript	c.1566-1G>T		splice_acceptor_variant		1	NM_001182.5	P4	P49419-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152110

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

250932

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000826

AC:

AN:

1451974

Hom.:

Cov.:

AF XY:

0.00000968

AC XY:

AN XY:

722978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000109

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000834

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyridoxine-dependent epilepsy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 29, 2023	This sequence change affects an acceptor splice site in intron 17 of the ALDH7A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 5 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in exon 18 (PMID: 23350806). ClinVar contains an entry for this variant (Variation ID: 374140). This variant is also known as c.1482-1G>T. Disruption of this splice site has been observed in individual(s) with pyridoxine dependent epilepsy (PMID: 17068770, 23350806). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs140845195, gnomAD 0.004%). -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2023	Observed in the homozygous state, with a pathogenic variant on the opposite allele (in trans), or with a second ALDH7A1 variant, phase unknown, in individuals with pyridoxine-dependent epilepsy in the published literature and not observed in homozygous state in controls (PMID: 30043187, 17068770); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Previously reported as c.1482-1 G>T due to alternative nomenclature; This variant is associated with the following publications: (PMID: 31589614, 29286531, 31990480, 17068770, 36011376, 30043187, 31440721, 31623504) -

Seizure;C3278923:Ventriculomegaly

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 15, 2015

- -

ALDH7A1-related condition

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2024

The ALDH7A1 c.1566-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in individuals with pyridoxine-dependent epilepsy (Plecko et al. 2007. PubMed ID: 17068770; Pérez et al. 2013. PubMed ID: 23350806; Coughlin et al. 2019. PubMed ID: 30043187. Table S2). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in ALDH7A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Pyridoxine-dependent epilepsy caused by ALDH7A1 mutant

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Sep 04, 2023

This sequence change in ALDH7A1 occurs within the canonical splice acceptor site of intron 17. It is predicted to cause the activation of the cryptic splice site in exon 18 leading to an in-frame five amino acid deletion (removes amino acids 495-499) which has been confirmed by RT-PCR on patient lymphoblast cells (PMID: 23350806). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.004% (4/113,332 alleles) in the European (non-Finnish) population. This variant has been detected in multiple individuals with pyridoxine-dependent epilepsy, homozygous and compound heterozygous with a second pathogenic variant (PMID: 23350806, 17068770, 31990480, 30043187). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Moderate, PM3_VeryStrong, PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.21

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D;D

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.78

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.78

Position offset: -1

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