rs750693623

Variant names:

• chr5-126595164-GC-G
• rs750693623
• NM_001182.5:c.34delG

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1 PM2 BS1_Supporting

The NM_001182.5(ALDH7A1):​c.34delG​(p.Ala12LeufsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,555,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: ALDH7A1 NM_001182.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6
• Conservation: PhyloP100: -1.96

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 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 89 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000525 (80/152348) while in subpopulation AFR AF= 0.00159 (66/41574). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.34delG	p.Ala12LeufsTer31	frameshift_variant	Exon 1 of 18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001202404.2	c.34delG	p.Ala12LeufsTer31	frameshift_variant	Exon 1 of 16		NP_001189333.2
ALDH7A1	NM_001201377.2	c.-51delG		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.34delG	p.Ala12LeufsTer31	frameshift_variant	Exon 1 of 18	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152230 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000112 AC: 18 AN: 160236 Hom.: 0 AF XY: 0.0000945 AC XY: 8 AN XY: 84674

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.000239

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000433

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000627 AC: 88 AN: 1402972 Hom.: 0 Cov.: 32 AF XY: 0.0000650 AC XY: 45 AN XY: 692492

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.000221

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000376

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000292

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152348 Hom.: 0 Cov.: 31 AF XY: 0.000524 AC XY: 39 AN XY: 74496

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000688

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pyridoxine-dependent epilepsy Pathogenic:1 Uncertain:1

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala12Leufs*31) in the ALDH7A1 gene. However, it is currently unclear if variants that occur in this region of the gene cause disease. This variant is present in population databases (rs750693623, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ALDH7A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 372663). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

May 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Apr 21, 2023

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALDH7A1 c.34delG (p.Ala12LeufsX31) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. However, as there is an alternative downstream in-frame start codon (p.Met29) which results in a different isoform, it is not clear whether variants within this region are likely to cause disease. The variant allele was found at a frequency of 0.00011 in 160236 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALDH7A1 causing Pyridoxine-Dependent Epilepsy (0.00011 vs 0.0018), allowing no conclusion about variant significance. c.34delG has been reported in the literature as a pathogenic variant in a heterozygous genotype among individuals within a cohort referred for diagnostic genetic testing for epilepsy (example, Truty_2019). Due to the lack of an informative genotype supporting recessive inheritance and no additional clinical or family history specifications, this report does not provide unequivocal conclusions about association of the variant with Pyridoxine-Dependent Epilepsy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30043187, 31440721). ClinVar contains an entry for this variant (Variation ID: 372663). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:2

Mar 23, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed as heterozygous variant in patients with epilepsy in published literature (Truty et al., 2019); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31440721) -

Inborn genetic diseases Uncertain:1

Jan 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34delG variant, located in coding exon 1 of the ALDH7A1 gene, results from a deletion of one nucleotide at nucleotide position 34, causing a translational frameshift with a predicted alternate stop codon (p.A12Lfs*31). The predicted stop codon occurs in the 5&rsquo; end of the ALDH7A1 gene. Premature termination codons in the 5&rsquo; end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). In addition, this variant is located upstream of an alternate in-frame translation initiation codon. Since this may result in expression of a different isoform and the biological contribution of each isoform is not well established, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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: rs750693623; hg19: chr5-125930856;