rs199673455
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_ModeratePP5_Moderate
The NM_005276.4(GPD1):c.686G>A(p.Arg229Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R229P) has been classified as Pathogenic.
Frequency
Consequence
NM_005276.4 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GPD1 | NM_005276.4 | c.686G>A | p.Arg229Gln | missense_variant | 6/8 | ENST00000301149.8 | NP_005267.2 | |
GPD1 | NM_001257199.2 | c.617G>A | p.Arg206Gln | missense_variant | 6/8 | NP_001244128.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GPD1 | ENST00000301149.8 | c.686G>A | p.Arg229Gln | missense_variant | 6/8 | 1 | NM_005276.4 | ENSP00000301149.3 | ||
GPD1 | ENST00000548814.1 | c.617G>A | p.Arg206Gln | missense_variant | 6/8 | 2 | ENSP00000446768.1 | |||
GPD1 | ENST00000547190.5 | n.656-384G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251480Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135914
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727240
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74448
ClinVar
Submissions by phenotype
Transient infantile hypertriglyceridemia and hepatosteatosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jul 22, 2023 | The missense c.686G>A p.Arg229Gln variant in the GPD1 gene has been reported previously in patients affected with Transient infantile hypertriglyceridemia Li, Jia-Qi et al.,2018. A different missense change p.Arg229Pro has been previously reported as likely pathogenic Joshi M, et al., 2014. This variant is reported with the allele frequency 0.006% in the gnomAD Exomes. The amino acid Arginine at position 229 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The amino acid Arginine in GPD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Functional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at