rs964724051
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000159.4(GCDH):c.700C>T(p.Arg234Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,746 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 (★★).
Frequency
Consequence
NM_000159.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.700C>T | p.Arg234Trp | missense_variant | Exon 8 of 12 | ENST00000222214.10 | NP_000150.1 | |
GCDH | NM_013976.5 | c.700C>T | p.Arg234Trp | missense_variant | Exon 8 of 12 | NP_039663.1 | ||
GCDH | NR_102316.1 | n.863C>T | non_coding_transcript_exon_variant | Exon 8 of 12 | ||||
GCDH | NR_102317.1 | n.1081C>T | non_coding_transcript_exon_variant | Exon 7 of 11 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461746Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727162
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:5Uncertain:1
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Variant summary: GCDH c.700C>T (p.Arg234Trp) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, central domain (IPR006091) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251420 control chromosomes. c.700C>T has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (e.g., Wang_2014, Pokora_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33728242, 30570710, 25190159). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (Pathogenic, n = 1; Likely pathogenic, n = 1; Uncertain significance, n = 1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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ClinVar contains an entry for this variant (Variation ID: 552581). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 25190159, 30570710; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 234 of the GCDH protein (p.Arg234Trp). -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at