rs1555751240
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000159.4(GCDH):c.1115G>A(p.Arg372Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 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).
Frequency
Consequence
NM_000159.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.1115G>A | p.Arg372Lys | missense_variant | Exon 11 of 12 | ENST00000222214.10 | NP_000150.1 | |
GCDH | NM_013976.5 | c.1115G>A | p.Arg372Lys | missense_variant | Exon 11 of 12 | NP_039663.1 | ||
GCDH | NR_102316.1 | n.1278G>A | non_coding_transcript_exon_variant | Exon 11 of 12 | ||||
GCDH | NR_102317.1 | n.1496G>A | non_coding_transcript_exon_variant | Exon 10 of 11 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727244
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:2Uncertain:1
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This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 372 of the GCDH protein (p.Arg372Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric acidemia type 1 (PMID: 10960496, 23395213; internal data). ClinVar contains an entry for this variant (Variation ID: 557606). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCDH protein function. 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