rs1553121073

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

DHDDS
NM_205861.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.96

Variant links:

Genes affected

DHDDS (HGNC:20603): (dehydrodolichyl diphosphate synthase subunit) The protein encoded by this gene catalyzes cis-prenyl chain elongation to produce the polyprenyl backbone of dolichol, a glycosyl carrier lipid required for the biosynthesis of several classes of glycoproteins. Mutations in this gene are associated with retinitis pigmentosa type 59. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

DHDDS links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_205861.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-26438213-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1214981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

PP5

Variant 1-26438214-G-A is Pathogenic according to our data. Variant chr1-26438214-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 451635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHDDS	NM_205861.3 link	c.110G>A	p.Arg37His	missense_variant	Exon 3 of 9	ENST00000236342.12	NP_995583.1	Q86SQ9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHDDS	ENST00000236342.12 link	c.110G>A	p.Arg37His	missense_variant	Exon 3 of 9	1	NM_205861.3	ENSP00000236342.7		Q86SQ9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental delay and seizures with or without movement abnormalities

Pathogenic:4

Jan 24, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 22, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS4, PP3, PM2 -

Nov 29, 2022

Laboratory of Medical Genetics, University of Torino

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Pathogenic:3

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 33057194, 35982159, 37356182, 38008000, 31780880, 29100083, 32654954, 36212160, 34382076) -

Retinitis pigmentosa 59

Pathogenic:1

Jun 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 451635). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

D;.;D;.;.;.;D;D;.;D;D;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.7

.;H;H;H;.;H;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.9

D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;D;D;.;D;.;.;.;.;.;.;.;.

Vest4

0.82

MutPred

0.70

Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);

MVP

0.74

MPC

1.6

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over