rs761491320
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000159.4(GCDH):βc.848delβ(p.Leu283ArgfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L283L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000159.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.848del | p.Leu283ArgfsTer8 | frameshift_variant | 8/12 | ENST00000222214.10 | |
GCDH | NM_013976.5 | c.848del | p.Leu283ArgfsTer8 | frameshift_variant | 8/12 | ||
GCDH | NR_102316.1 | n.1011del | non_coding_transcript_exon_variant | 8/12 | |||
GCDH | NR_102317.1 | n.1229del | non_coding_transcript_exon_variant | 7/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCDH | ENST00000222214.10 | c.848del | p.Leu283ArgfsTer8 | frameshift_variant | 8/12 | 1 | NM_000159.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.0000366 AC: 9AN: 246168Hom.: 0 AF XY: 0.0000374 AC XY: 5AN XY: 133644
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460172Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726358
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 10, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 22, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change creates a premature translational stop signal (p.Leu283Argfs*8) in the GCDH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GCDH are known to be pathogenic (PMID: 10699052, 11854167, 16602100). This variant is present in population databases (rs761491320, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with glutaric acidemia type I (PMID: 26316201, 29086383). ClinVar contains an entry for this variant (Variation ID: 370672). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at