chr5-126552059-C-G

Variant names:

• chr5-126552059-C-G
• rs121912707
• NM_001182.5:c.1279G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM5 PP2 PP3 PP5_Very_Strong

The NM_001182.5(ALDH7A1):​c.1279G>C​(p.Glu427Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,613,960 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000551314: Experimental studies have shown that this missense change affects ALDH7A1 function (PMID:16491085)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E427G) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35 O:1
• Conservation: PhyloP100: 7.79
• Publications: 53 publications found

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: Orphanet, Illumina, ClinGen
• pyridoxine-dependent epilepsy caused by ALDH7A1 mutant

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000551314: Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 16491085).; SCV000711784: "In vitro functional studies provide evidence that the p.Glu427Gln variant impacts protein function." PMID:16491085, PMID:22784480; SCV000916081: Functional studies using transfected CHO cells were performed by Mills et al. (2006) and found α-AASA dehydrogenase activity to be undetectable. Coulter-Mackie et al. (2012) used transfected E. coli and observed enzyme activity levels below the level of detection for the assay.; SCV000996079: Functional studies have shown that the p.Glu427Gln results in an absence of detectable enzyme activity in a CHO in vitro cell model (PMID: 16491085).; SCV002059141: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 16491085, 22784480)."; SCV002495769: "functional studies utilizing chinese hamster ovary cells and e.coli assays have shown a deleterious effect of this variant." PMID:16491085, PMID:22784480; SCV004564843: "In support of these predictions, functional analyses show an effect of this variant on enzyme activity (Coulter-Mackie 2012)." PMID: 22784480; SCV006086136: Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated undetectable activity for the variant protein (e.g. Mills_2006, Coulter-Mackie_2012). PMID: 16491085, 17068770, 22784480; SCV000240311: Published functional studies demonstrate the variant abolishes enzyme activity (Mills et al., 2006; Coulter-Mackie et al., 2012); SCV006328276: PS3:Supporting; SCV000849306: Enzyme activity in transfected CHO cells and E. coli cells have demonstrated undetectable or extremely low (<3% of WT) enzyme activity (Mills PB et al. Nat. Med., 2006 Mar;12:307-9; Coulter-Mackie MB et al. Mol. Genet. Metab., 2012 Aug;106:478-81).; SCV002507017: "In vitro functional studies provide some evidence that the p.Glu427Gln variant may impact protein function (PMID: 22784480, 16491085)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_001182.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-126552058-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 944165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 caused by ALDH7A1 mutant, pyridoxine-dependent epilepsy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78
• PP5: Variant 5-126552059-C-G is Pathogenic according to our data. Variant chr5-126552059-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001182.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH7A1	NM_001182.5	MANE Select	c.1279G>C	p.Glu427Gln	missense	Exon 14 of 18	NP_001173.2	P49419-1
	ALDH7A1	NM_001201377.2		c.1195G>C	p.Glu399Gln	missense	Exon 14 of 18	NP_001188306.1	P49419-2
	ALDH7A1	NM_001202404.2		c.1087G>C	p.Glu363Gln	missense	Exon 12 of 16	NP_001189333.2	P49419-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH7A1	ENST00000409134.8	TSL:1 MANE Select	c.1279G>C	p.Glu427Gln	missense	Exon 14 of 18	ENSP00000387123.3	P49419-1
	ALDH7A1	ENST00000636879.1	TSL:5	c.1324G>C	p.Glu442Gln	missense	Exon 15 of 19	ENSP00000490811.1	A0A1B0GW77
	ALDH7A1	ENST00000939100.1		c.1321G>C	p.Glu441Gln	missense	Exon 15 of 19	ENSP00000609159.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000358 AC: 90 AN: 251230 AF XY: 0.000361

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000543 AC: 793 AN: 1461696 Hom.: 0 Cov.: 32 AF XY: 0.000532 AC XY: 387 AN XY: 727150

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5676

European-Non Finnish (NFE) AF: 0.000673 AC: 748 AN: 1111968

Other (OTH) AF: 0.000431 AC: 26 AN: 60376

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74464

African (AFR) AF: 0.000120 AC: 5 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000499 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
26	-	-	Pyridoxine-dependent epilepsy (27)
6	-	-	not provided (6)
2	-	-	Seizure (2)
1	-	-	Pyridoxine-dependent epilepsy caused by ALDH7A1 mutant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		7.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.013	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.99
MPC		0.60
ClinPred		0.35	T
GERP RS		4.9
Varity_R		0.93
gMVP		0.97
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912707; hg19: chr5-125887751;