rs1553121073
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_205861.3(DHDDS):c.110G>A(p.Arg37His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37C) has been classified as Pathogenic.
Frequency
Consequence
NM_205861.3 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHDDS | NM_205861.3 | c.110G>A | p.Arg37His | missense_variant | 3/9 | ENST00000236342.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHDDS | ENST00000236342.12 | c.110G>A | p.Arg37His | missense_variant | 3/9 | 1 | NM_205861.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Developmental delay and seizures with or without movement abnormalities Pathogenic:4Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 24, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | This missense variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.49). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000451635). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29100083 , 29100083). A different missense change at the same codon (p.Arg37Cys) has been reported to be associated with DHDDS-related disorder (ClinVar ID: VCV001214981). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 03, 2021 | Despite strong evidence for its pathogenicity, this variant has to be classified as of unknown significance, according to the ACMG-criteria (Richards et al., 2015) - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Dec 22, 2021 | PS2, PS4, PP3, PM2 - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Medical Genetics, University of Torino | Nov 29, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2020 | Not observed in large population cohorts (Lek et al., 2016) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function This variant is associated with the following publications: (PMID: 29100083, 31780880) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
Retinitis pigmentosa 59 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 451635). This missense change has been observed in individual(s) with autosomal dominant developmental and epileptic encephalopathy (PMID: 29100083, 31780880). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 37 of the DHDDS protein (p.Arg37His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at