rs758503371
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000159.4(GCDH):c.764C>T(p.Ser255Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,132 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S255P) has been classified as Pathogenic.
Frequency
Consequence
NM_000159.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.764C>T | p.Ser255Leu | missense_variant | 8/12 | ENST00000222214.10 | |
GCDH | NM_013976.5 | c.764C>T | p.Ser255Leu | missense_variant | 8/12 | ||
GCDH | NR_102316.1 | n.927C>T | non_coding_transcript_exon_variant | 8/12 | |||
GCDH | NR_102317.1 | n.1145C>T | non_coding_transcript_exon_variant | 7/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCDH | ENST00000222214.10 | c.764C>T | p.Ser255Leu | missense_variant | 8/12 | 1 | NM_000159.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251318Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135864
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461860Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727232
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74440
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Mar 17, 2022 | ACMG classification criteria: PS4 strong, PM2, PM3 strong, PM5 moderated, PP1 supporting, PP3 supporting, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 10, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 19, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 255 of the GCDH protein (p.Ser255Leu). This variant is present in population databases (rs758503371, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaryl-CoA dehydrogenase deficiency (PMID: 10960496, 25204480, 25762492, 27351573). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374435). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCDH protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 26, 2018 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at