rs1553121073

chr1-26438214-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

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: Genomes: not found (cov: 32)
• Consequence: DHDDS NM_205861.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 9.96

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 451635.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Likely_pathogenic=1, Uncertain_significance=1}.

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

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental delay and seizures with or without movement abnormalities Pathogenic:4 Uncertain:1

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	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. -
Pathogenic, criteria provided, single submitter	research	Laboratory of Medical Genetics, University of Torino	Nov 29, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 24, 2018	- -
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) -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
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) -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	34
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	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
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	D
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

Other links and lift over

dbSNP: rs1553121073; hg19: chr1-26764705; COSMIC: COSV52578667; COSMIC: COSV52578667;