5-126559262-C-T

Variant names:

• chr5-126559262-C-T
• rs864622558
• NM_001182.5:c.986G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001182.5(ALDH7A1):​c.986G>A​(p.Arg329Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.89

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 5-126559262-C-T is Pathogenic according to our data. Variant chr5-126559262-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 220512.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-126559262-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.986G>A	p.Arg329Lys	missense_variant	Exon 11 of 18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2	c.902G>A	p.Arg301Lys	missense_variant	Exon 11 of 18		NP_001188306.1
ALDH7A1	NM_001202404.2	c.986G>A	p.Arg329Lys	missense_variant	Exon 11 of 16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.986G>A	p.Arg329Lys	missense_variant	Exon 11 of 18	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyridoxine-dependent epilepsy Pathogenic:1

Jan 09, 2024

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 lysine, which is basic and polar, at codon 329 of the ALDH7A1 protein (p.Arg329Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with elevated urine alpha-AASA and pyridoxine-responsive seizures (PMID: 31737911; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 220512). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;D;.;T;.;.;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.9	.;M;.;.;.;.;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.0	.;D;.;.;.;.;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	.;D;.;.;.;.;D;.
Sift4G	Pathogenic	0.0010	.;D;.;.;.;.;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.73, 0.74
MutPred		0.66		Gain of methylation at R329 (P = 0.0203);Gain of methylation at R329 (P = 0.0203);.;.;.;.;Gain of methylation at R329 (P = 0.0203);.;
MVP		0.95
MPC		0.65
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs864622558; hg19: chr5-125894954;