rs1270423610
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001182.5(ALDH7A1):c.796C>T(p.Arg266Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000116 in 1,461,794 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: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
ALDH7A1
NM_001182.5 stop_gained
NM_001182.5 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.11
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 5-126568334-G-A is Pathogenic according to our data. Variant chr5-126568334-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 465333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126568334-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH7A1 | NM_001182.5 | c.796C>T | p.Arg266Ter | stop_gained | 9/18 | ENST00000409134.8 | |
ALDH7A1 | NM_001201377.2 | c.712C>T | p.Arg238Ter | stop_gained | 9/18 | ||
ALDH7A1 | NM_001202404.2 | c.796C>T | p.Arg266Ter | stop_gained | 9/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH7A1 | ENST00000409134.8 | c.796C>T | p.Arg266Ter | stop_gained | 9/18 | 1 | NM_001182.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251476Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135910
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461794Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727200
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pyridoxine-dependent epilepsy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 07, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change creates a premature translational stop signal (p.Arg266*) 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 (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with pyridoxine-dependent epilepsy (PMID: 19128417, 20554659). This variant is also known as c.712C>T (p.R238X). ClinVar contains an entry for this variant (Variation ID: 465333). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2020 | Observed multiple times with a pathogenic variant in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases ([described as R238X due to the use of alternative nomenclature]; Mathis et al., 2016; Xue et al., 2015; Oesch et al., 2018); 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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 29401530, 29875223, 19128417, 27342130, 26555630, 31737911, 20554659, 30043187) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2017 | - - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 19, 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
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
0.92, 0.91, 0.92
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 22
Find out detailed SpliceAI scores and Pangolin per-transcript scores at