rs1554097854

Variant names:

• chr5-126546330-G-A
• rs1554097854
• NM_001182.5:c.1559C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001182.5(ALDH7A1):​c.1559C>T​(p.Ser520Phe) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.49
• Publications: 0 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: Illumina, Orphanet, ClinGen
• pyridoxine-dependent epilepsy caused by ALDH7A1 mutant

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001182.5
• PM2: Very rare variant in population databases, with high coverage
• 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, pyridoxine-dependent epilepsy caused by ALDH7A1 mutant.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 5-126546330-G-A is Pathogenic according to our data. Variant chr5-126546330-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465325.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.1559C>T	p.Ser520Phe	missense_variant	Exon 17 of 18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2	c.1475C>T	p.Ser492Phe	missense_variant	Exon 17 of 18		NP_001188306.1
ALDH7A1	NM_001202404.2	c.1367C>T	p.Ser456Phe	missense_variant	Exon 15 of 16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.1559C>T	p.Ser520Phe	missense_variant	Exon 17 of 18	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pyridoxine-dependent epilepsy Pathogenic:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 520 of the ALDH7A1 protein (p.Ser520Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pyridoxine-responsive seizures (internal data). ClinVar contains an entry for this variant (Variation ID: 465325). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ALDH7A1 protein function with a positive predictive value of 95%. This variant disrupts the p.Ser520 amino acid residue in ALDH7A1. Other variant(s) that disrupt this residue have been observed in individuals with ALDH7A1-related conditions (PMID: 23350806), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Uncertain:1

Mar 26, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S520F variant (also known as c.1559C>T), located in coding exon 17 of the ALDH7A1 gene, results from a C to T substitution at nucleotide position 1559. The serine at codon 520 is replaced by phenylalanine, an amino acid with highly dissimilar properties. Another variant at the same position (reported as p.S492P) was reported in the homozygous state in an individual with ALDH7A1 deficiency (Pérez B et al. Epilepsia, 2013 Feb;54:239-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Oct 03, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37580162) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;D;T;.;T;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.6	.;H;.;.;.;.;.;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	.;D;.;.;.;.;.;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	.;D;.;.;.;.;.;D
Sift4G	Uncertain	0.037	.;D;.;.;.;.;.;T
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.97, 0.97
MutPred		0.61		Loss of catalytic residue at S520 (P = 0.0297);Loss of catalytic residue at S520 (P = 0.0297);.;.;.;.;.;.;
MVP		0.99
MPC		0.69
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.97
gMVP		0.73
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1554097854; hg19: chr5-125882022;