rs121912708

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001182.5(ALDH7A1):c.328C>T(p.Arg110Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,902 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R110R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

ALDH7A1
NM_001182.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 2.61

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 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-126583997-G-A is Pathogenic according to our data. Variant chr5-126583997-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126583997-G-A is described in Lovd as [Pathogenic]. Variant chr5-126583997-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALDH7A1	NM_001182.5 linkuse as main transcript	c.328C>T	p.Arg110Ter	stop_gained	4/18	ENST00000409134.8
ALDH7A1	NM_001201377.2 linkuse as main transcript	c.244C>T	p.Arg82Ter	stop_gained	4/18
ALDH7A1	NM_001202404.2 linkuse as main transcript	c.328C>T	p.Arg110Ter	stop_gained	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH7A1	ENST00000409134.8 linkuse as main transcript	c.328C>T	p.Arg110Ter	stop_gained	4/18	1	NM_001182.5	P4	P49419-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251464

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000122

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyridoxine-dependent epilepsy

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Nov 02, 2017	The p.Arg119Ter variant (also referred to as p.Arg82Ter in the literature) is a stop-gained variant that is predicted to result in the premature truncation of the ALDH7A1 protein. This variant has been reported in two patients, once in the homozygous state and once in the compound heterozygous state that is identical to that seen in this patient (PMID: 16491085). This variant combination was shown to result in an absence of enzyme activity via in vitro functional expression studies in Chinese hamster ovary cells (PMID: 16491085). The highest reported allele frequency in the population database, gnomAD, is 0.0001 (13/126702 alleles). Based on the available evidence, the p.Arg119Ter variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change creates a premature translational stop signal (p.Arg110*) in the ALDH7A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH7A1 are known to be pathogenic (PMID: 16491085, 20554659). This variant is present in population databases (rs121912708, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with pyridoxine-dependent seizures (PMID: 16491085, 18717709, 26101365, 26232297). This variant is also known as c.244C>T, p.Arg82X. ClinVar contains an entry for this variant (Variation ID: 17995). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 05, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ALDH7A1: PM3:Very Strong, PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2021	Published functional studies demonstrate a damaging effect showing that the mutant enzyme had no detectable activity compared to wild type (Mills et al., 2006); 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; This variant is associated with the following publications: (PMID: 18717709, 29875223, 30043187, 16491085, 31019026, 25525159, 26101365, 26232297, 27342130, 29286531, 31564432, 31623504, 31990480) -

Seizure;C3278923:Ventriculomegaly

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 15, 2015

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2022

The c.328C>T (p.R110*) alteration, located in exon 4 (coding exon 4) of the ALDH7A1 gene, consists of a C to T substitution at nucleotide position 328. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 110. 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 0.01% (18/282868) total alleles studied. The highest observed frequency was 0.01% (1/7222) of Other alleles. This alteration has been reported in the homozygous and compound heterozygous states in multiple individuals with pyridoxine-dependent epilepsy (Cirillo, 2015; Kingsmore, 2019; Mills, 2006; Tincheva, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 25, 2021

ACMG classification criteria: PVS1, PS4, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.57

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.90

MutationTaster

Benign

1.0

A;A;A

Vest4

0.92, 0.81, 0.95

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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