chr5-126583997-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001182.5(ALDH7A1):c.328C>T(p.Arg110*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,902 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )
Consequence
ALDH7A1
NM_001182.5 stop_gained
NM_001182.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.61
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-126583997-G-A is Pathogenic according to our data. Variant chr5-126583997-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126583997-G-A is described in Lovd as [Pathogenic]. Variant chr5-126583997-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ALDH7A1 | NM_001182.5 | c.328C>T | p.Arg110* | stop_gained | 4/18 | ENST00000409134.8 | NP_001173.2 | |
| ALDH7A1 | NM_001201377.2 | c.244C>T | p.Arg82* | stop_gained | 4/18 | NP_001188306.1 | ||
| ALDH7A1 | NM_001202404.2 | c.328C>T | p.Arg110* | stop_gained | 4/16 | NP_001189333.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ALDH7A1 | ENST00000409134.8 | c.328C>T | p.Arg110* | stop_gained | 4/18 | 1 | NM_001182.5 | ENSP00000387123.3 |
Frequencies
GnomAD3 genomes 0.0000986 AC: 15AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251464Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135904
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GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461740Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 727170
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GnomAD4 genome 0.0000986 AC: 15AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74330
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pyridoxine-dependent epilepsy Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Nov 02, 2017 | The p.Arg119Ter variant (also referred to as p.Arg82Ter in the literature) is a stop-gained variant that is predicted to result in the premature truncation of the ALDH7A1 protein. This variant has been reported in two patients, once in the homozygous state and once in the compound heterozygous state that is identical to that seen in this patient (PMID: 16491085). This variant combination was shown to result in an absence of enzyme activity via in vitro functional expression studies in Chinese hamster ovary cells (PMID: 16491085). The highest reported allele frequency in the population database, gnomAD, is 0.0001 (13/126702 alleles). Based on the available evidence, the p.Arg119Ter variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2006 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 17, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 05, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Arg110*) in the ALDH7A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALDH7A1 are known to be pathogenic (PMID: 16491085, 20554659). This variant is present in population databases (rs121912708, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with pyridoxine-dependent seizures (PMID: 16491085, 18717709, 26101365, 26232297). This variant is also known as c.244C>T, p.Arg82X. ClinVar contains an entry for this variant (Variation ID: 17995). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 10, 2024 | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with epilepsy, early-onset, 4, vitamin B6-dependent (MIM#266100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (76 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as pathogenic or likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported eleven times as pathogenic by clinical testing laboratories (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | ALDH7A1: PM3:Very Strong, PVS1, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2024 | Published functional studies demonstrate a damaging effect showing that the mutant enzyme had no detectable activity compared to wild type (PMID: 16491085); Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18717709, 29875223, 30043187, 34645491, 31440721, 31019026, 25525159, 29286531, 31564432, 31623504, 31990480, 34426522, 34569664, 38250573, 16491085, 26232297, 26101365, 27342130) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 28, 2017 | - - |
Seizure;C3278923:Ventriculomegaly Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 15, 2015 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2022 | The c.328C>T (p.R110*) alteration, located in exon 4 (coding exon 4) of the ALDH7A1 gene, consists of a C to T substitution at nucleotide position 328. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 110. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.01% (18/282868) total alleles studied. The highest observed frequency was 0.01% (1/7222) of Other alleles. This alteration has been reported in the homozygous and compound heterozygous states in multiple individuals with pyridoxine-dependent epilepsy (Cirillo, 2015; Kingsmore, 2019; Mills, 2006; Tincheva, 2015). Based on the available evidence, this alteration is classified as pathogenic. - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Mar 25, 2021 | ACMG classification criteria: PVS1, PS4, PM2, PM3 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
0.92, 0.81, 0.95
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at