ClinVar Genomic variation as it relates to human health
NM_205861.3(DHDDS):c.614G>A (p.Arg205Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_205861.3(DHDDS):c.614G>A (p.Arg205Gln)
Variation ID: 570739 Accession: VCV000570739.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.11 1: 26457862 (GRCh38) [ NCBI UCSC ] 1: 26784353 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 10, 2018 Feb 14, 2024 Oct 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_205861.3:c.614G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_995583.1:p.Arg205Gln missense NM_001243564.2:c.512G>A NP_001230493.1:p.Arg171Gln missense NM_001243565.2:c.497G>A NP_001230494.1:p.Arg166Gln missense NM_001319959.2:c.335G>A NP_001306888.1:p.Arg112Gln missense NM_024887.4:c.614G>A NP_079163.2:p.Arg205Gln missense NC_000001.11:g.26457862G>A NC_000001.10:g.26784353G>A NG_029786.1:g.30581G>A - Protein change
- R205Q, R171Q, R112Q, R166Q
- Other names
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- Canonical SPDI
- NC_000001.11:26457861:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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DHDDS | - | - |
GRCh38 GRCh37 |
545 | 554 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2023 | RCV000691673.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2022 | RCV001539674.4 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jul 26, 2023 | RCV002233230.7 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Apr 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental delay and seizures with or without movement abnormalities
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511891.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: DHDDS c.614G>A (p.Arg205Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: DHDDS c.614G>A (p.Arg205Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251480 control chromosomes. c.614G>A has been reported in the literature in individuals affected with Developmental Delay And Seizures With Or Without Movement Abnormalities with de novo inheritance (Wood_2021, Jiao_2022, Galosi_2022), and once with unknown inheritance (Courage_2021). These data indicate that the variant is likely to be associated with disease. Functional studies on patient fibroblasts showed decreased membrane cisPTase activity, altered levels of ICAM1 and LAMP1 proteins and cholesterol accumulation, consistent with a protein N-glycosylation defect (Courage_2021). Additionally, DHDDS-P233R did not support yeast growth in cells lacking endogenous genes critical for cis-PTase activity, further confirming their predicted essential role in enzymatic activity (Galosi_2022). This Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental delay and seizures with or without movement abnormalities
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Fundacion Publica Galega de Medicina Xenomica, Servicio Galego de Saude
Accession: SCV002584525.3
First in ClinVar: Oct 22, 2022 Last updated: Nov 13, 2022 |
Comment:
DHDDS(NM_205861.3):c.614G>A p.(Arg205Gln) is a missense variant considered deleterious to DHDDS protein function or structure by most bioinformatic predictors, which has been corroborated by functional studies … (more)
DHDDS(NM_205861.3):c.614G>A p.(Arg205Gln) is a missense variant considered deleterious to DHDDS protein function or structure by most bioinformatic predictors, which has been corroborated by functional studies (PMID: 33798445). The variant is not reported in population frequency databases but has been reported in the literature in individuals affected with Developmental Delay And Seizures With Or Without Movement Abnormalities with de novo inheritance (PMID: 34275143, 34182312, 34382076). Variants of this type in DHDDS gene, even in the same exon, have been classified as pathogenic for DEVELOPMENTAL DELAY AND SEIZURES WITH OR WITHOUT MOVEMENT ANOMALIES (OMIM 617836). In our case was confirmed as de novo in a patient with consistent phenotype and no family history. With the currently available evidence this variant is considered pathogenic according to ACMG + ACGS guidelines (Class 5). (less)
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Pathogenic
(Jan 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001757474.3
First in ClinVar: Jul 24, 2021 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 33798445, 34382076, 34182312, 34837344, 34275143) (less)
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Pathogenic
(Dec 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Developmental delay and seizures with or without movement abnormalities
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004014735.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The DHDDS c.614G>A (p.Arg205Gln) missense variant results in the substitution of arginine at amino acid position 205 with glutamine. This variant has been reported in … (more)
The DHDDS c.614G>A (p.Arg205Gln) missense variant results in the substitution of arginine at amino acid position 205 with glutamine. This variant has been reported in a heterozygous state in six individuals with features of developmental delay and seizures with or without movement abnormalities in the peer-reviewed literature, occurring de novo in at least two cases and in a familial case in an affected mother and two daughters (PMID: 33798445; PMID: 34182312; PMID: 34275143; PMID: 34382076). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies have demonstrated that yeast harboring the c.614G>A variant show growth deficiency and low cis-PTase activity compared to wild type yeast (PMID: 34382076). The variant was identified in a de novo state. Based on the available evidence, the c.614G>A (p.Arg205Gln) variant is classified as pathogenic for developmental delay and seizures with or without movement abnormalities. (less)
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Pathogenic
(Mar 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental delay and seizures with or without movement abnormalities
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041136.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Jul 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental delay and seizures with or without movement abnormalities
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004099243.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
PS3, PS4_Moderate, PM2, PM6, PP3
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Pathogenic
(Oct 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Retinitis pigmentosa 59
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000819461.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 205 of the DHDDS protein (p.Arg205Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 205 of the DHDDS protein (p.Arg205Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 33798445, 34182312; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 570739). 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 DHDDS protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus. | Galosi S | Brain : a journal of neurology | 2022 | PMID: 34382076 |
Phenotype of heterozygous variants of dehydrodolichol diphosphate synthase. | Jiao X | Developmental medicine and child neurology | 2022 | PMID: 34275143 |
DHDDS related epilepsy--Report of familial cases and review of the literature. | Wood K | Seizure | 2021 | PMID: 34182312 |
Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes. | Courage C | American journal of human genetics | 2021 | PMID: 33798445 |
Text-mined citations for rs1557447255 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.