rs794726972
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_000159.4(GCDH):āc.997C>Gā(p.Gln333Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,586 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q333R) has been classified as Pathogenic.
Frequency
Consequence
NM_000159.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.997C>G | p.Gln333Glu | missense_variant | 10/12 | ENST00000222214.10 | |
GCDH | NM_013976.5 | c.997C>G | p.Gln333Glu | missense_variant | 10/12 | ||
GCDH | NR_102316.1 | n.1160C>G | non_coding_transcript_exon_variant | 10/12 | |||
GCDH | NR_102317.1 | n.1378C>G | non_coding_transcript_exon_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCDH | ENST00000222214.10 | c.997C>G | p.Gln333Glu | missense_variant | 10/12 | 1 | NM_000159.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461586Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727110
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2018 | The Q333E missense change in the GCDH gene has been previously reported as disease-causing (Goodman et al., 1998). Q333E is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. It occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The Q333E variant is predicted to be located on the surface of the GCDH gene and to be involved in GCDH homotetramerisation; approximately 20% of missense variants reported in association with GA1 are located on the surface of GCDH, supporting the functional importance of this region of the protein (Schmiesing et al., 2017). In summary, we interpret Q333E as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 27, 2015 | - - |
Glutaric aciduria, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This sequence change replaces glutamine with glutamic acid at codon 333 of the GCDH protein (p.Gln333Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with glutaric aciduria (PMID: 9711871). ClinVar contains an entry for this variant (Variation ID: 193561). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 02, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at