NM_001182.5:c.31_33delCACinsGAG

Variant names:

• chr5-126595166-GTG-CTC
• rs796052269
• NM_001182.5:c.31_33delCACinsGAG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP2 BP6

The NM_001182.5(ALDH7A1):​c.31_33delCACinsGAG​(p.His11Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.000105 in 20 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H11Q) has been classified as Likely benign.

• Frequency: GnomAD MNV: 𝑓 0.00011 Genomes: not found (cov: 31)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.54
• 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: Uncertain_significance. The variant received 0 ACMG points.

• 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.
• BP6: Variant 5-126595166-GTG-CTC is Benign according to our data. Variant chr5-126595166-GTG-CTC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204861.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.31_33delCACinsGAG	p.His11Glu	missense_variant		ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001202404.2	c.31_33delCACinsGAG	p.His11Glu	missense_variant			NP_001189333.2
ALDH7A1	NM_001201377.2	c.-54_-52delCACinsGAG		5_prime_UTR_variant	Exon 1 of 18		NP_001188306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.31_33delCACinsGAG	p.His11Glu	missense_variant		1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

GnomAD MNV AF: 0.000105 AC: 20 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Jan 05, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.31_33delCACinsGAG: p.His11Glu (H11E) in exon 1 of the ALDH7A1 gene (NM_001182.4). The normal sequence with the bases that are deleted in braces followed by the inserted bases in brackets is: CTGTGTGTG{CAC}[GAG] GCTG. The c.31_33delCACinsGAG variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The c.31_33delCACinsGAG variant results in an in-frame deletion of a single Histidine residue and the insertion of a single Glutamic acid residue, denoted p.His11Glu (H11E). The H11E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -

Inborn genetic diseases Uncertain:1

Jun 12, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31_33delCACinsGAG variant, located in coding exon 1 of the ALDH7A1 gene, results from an in-frame deletion of CAC and insertion of GAG at nucleotide positions 31 to 33. This results in the substitution of the histidine residue for a glutamic acid residue at codon 11, an amino acid with highly similar properties. Based on data from gnomAD, this alteration was deposited as two separate missense substitutions (c.31C>G; c.33C>G) each with an overall frequency of approximately 0.01% (21/184172; 20/183384) total alleles studied. The highest observed frequency for each was approximately 0.07% (19/25066; 18/25014) of Latino alleles. This amino acid position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Pyridoxine-dependent epilepsy Benign:1

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs796052269; hg19: chr5-125930858;