chr5-126577199-G-T

Position:

• chr5-126577199-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2 PM5 PP5_Very_Strong BP4

The NM_001182.5(ALDH7A1):​c.530C>A​(p.Ala177Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A177P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.86

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-126577200-C-G is described in Lovd as [Pathogenic].
• PP5: Variant 5-126577199-G-T is Pathogenic according to our data. Variant chr5-126577199-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126577199-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.391619). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.530C>A	p.Ala177Glu	missense_variant	6/18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2	c.446C>A	p.Ala149Glu	missense_variant	6/18		NP_001188306.1
ALDH7A1	NM_001202404.2	c.530C>A	p.Ala177Glu	missense_variant	6/16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.530C>A	p.Ala177Glu	missense_variant	6/18	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251402 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135876

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: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727234

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: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyridoxine-dependent epilepsy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	The observed missense c.530C>A (p.Ala177Glu) variant in ALDH7A1 gene has been reported in multiple individuals affected with epilepsy (Mills et al., 2010; Jain-Ghai et al., 2014; Coughlin et al., 2019; Korasick and Tanner, 2021). This variant is present with allele frquency of 0.0008% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. Computational evidence (Polyphen - Possibly Damaging, SIFT - Tolerated and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid of p.Ala177Glu in ALDH7A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 177 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. However, in absence of another reportable variant in ALDH7A1 gene, the molecular diagnosis is not confirmed. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 177 of the ALDH7A1 protein (p.Ala177Glu). This variant is present in population databases (rs764417585, gnomAD 0.006%). This missense change has been observed in individual(s) with pyridoxine dependent epilepsy (PMID: 20554659, 24664088). 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: 410537). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALDH7A1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.0020	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.074	T;D;T;.;T;.;.;.;T;T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.097	D
MutationAssessor	Benign	1.3	.;L;.;.;.;.;.;L;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	.;N;.;.;.;.;.;N;.;.;N;.
REVEL	Uncertain	0.46
Sift	Benign	0.21	.;T;.;.;.;.;.;T;.;.;T;.
Sift4G	Benign	0.15	.;T;.;.;.;.;.;T;.;T;.;.
Polyphen		0.95	.;P;.;.;.;.;.;.;.;.;.;.
Vest4		0.73, 0.74, 0.73
MutPred		0.59		Gain of disorder (P = 0.0098);Gain of disorder (P = 0.0098);Gain of disorder (P = 0.0098);Gain of disorder (P = 0.0098);.;.;.;Gain of disorder (P = 0.0098);.;Gain of disorder (P = 0.0098);.;.;
MVP		0.91
MPC		0.47
ClinPred		0.68	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.79

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: rs764417585; hg19: chr5-125912891;