rs147394623

chr1-26438228-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1 PP3 PP5_Very_Strong BP4

The NM_205861.3(DHDDS):c.124A>G(p.Lys42Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K42R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DHDDS NM_205861.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 9.29

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_205861.3
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, phyloP100way_vertebrate, REVEL [when max_spliceai, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
• PP5: Variant 1-26438228-A-G is Pathogenic according to our data. Variant chr1-26438228-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 30709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-26438228-A-G is described in Lovd as [Pathogenic]. Variant chr1-26438228-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-26438228-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.10075554).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHDDS	NM_205861.3	c.124A>G	p.Lys42Glu	missense_variant	3/9	ENST00000236342.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHDDS	ENST00000236342.12	c.124A>G	p.Lys42Glu	missense_variant	3/9	1	NM_205861.3	P4

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152266 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251490 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1461728 Hom.: 0 Cov.: 31 AF XY: 0.000124 AC XY: 90 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00555

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74388

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000275 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 59 Pathogenic:9

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	The heterozygous p.Lys42Glu variant in DHDDS was identified by our study in an assumed compound heterozygous state with unknown phase, along with a likely pathogenic variant, in 1 individual with retinitis pigmentosa 59. The variant has been reported in at least 20 Ashkenazi Jewish individuals with retinitis pigmentosa, segregated with disease in 6 affected relatives from 5 families (PMID: 21295282, 21295283), and has been identified in 0.52% (54/10370) of Ashkenazi Jewish, 0.004% (5/129194) of European non-Finnish, and 0.003% (1/35440) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs147394623). This variant has also been reported in ClinVar (Variation ID: 30709) and has been interpreted as pathogenic by multiple labs. In vitro functional studies provide some evidence that the variant may slightly impact protein function (PMID: 25066056, 27343064). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in at least 20 affected homozygotes with retinitis pigmentosa increases the likelihood that the variant is pathogenic (PMID: 21295282, 21295283, 28130426, 29276052, 25255364, 24078709). The p.Lys42Glu variant is located in a region of DHDDS that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 21295283). In summary, this variant meets criteria to be classified as pathogenic for retinitis pigmentosa 59 in an autosomal recessive manner based on high allele frequency and disease cosegregation in a founder population, the predicted impact of the variant, and a high number of affected homozygotes. ACMG/AMP Criteria applied: PP1_strong, PM2, PS3_supporting, PM3, PM1_supporting (Richards 2015). -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_024887.3:c.124A>G in the DHDDS gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. Functional studies have shown that p.Lys42Glu (NM_024887.3:c.124A>G) results in a DHDDS protein with decreased enzyme activity (PMID: 25066056). Zelinger et al. repoted p.Lys42Glu homozygous in 15 Ashkenazi Jews patients with Retinitis pigmentosa, and the phenotypes cosegregates with genotypes (PMID: 21295282); In addition, Zuchner et al also reported a pedigree of a non-consanguineous family with three affected offspring, harboring the homozygous of this variant (PMID: 21295283).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3_Strong; PP1. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 11, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2016	Variant summary: The DHDDS c.124A>G (p.Lys42Glu) variant located in close proximity to the catalytic center and the substrate binding site for farnesyl pyrophosphate phosphate (FPP of the enzyme) causes a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index predict a damaging outcome ) predicting a "benign" outcome. However, functional studies conflict these with in silico predictions and show that K42E results in a 75% reduction in cis-PTase enzyme activity. This variant was found in 25/149220 control chromosomes at a frequency of 0.0001675, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHDDS variant (0.0007906). Multiple publications cite the variant in affected individuals in a homozygous state, and it has been implicated as an Ashkenazi Jewish founder mutation for retinitis pigmentosa. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Taken together, the variant of interest has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The DHDDS c.124A>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PM3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_024887.3(DHDDS):c.124A>G(K42E) is classified as pathogenic in the context of retinitis pigmentosa type 59. Sources cited for classification include the following: PMID 22110072, 21295282, 24664694 and 27343064. Classification of NM_024887.3(DHDDS):c.124A>G(K42E) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 42 of the DHDDS protein (p.Lys42Glu). This variant is present in population databases (rs147394623, gnomAD 0.5%). This missense change has been observed in individuals with autosomal recessive retinitis pigmentosa (PMID: 21295282, 21295283, 24664694, 28130426). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 21295282, 21295283, 24664694, 28130426). ClinVar contains an entry for this variant (Variation ID: 30709). 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 not expected to disrupt DHDDS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects DHDDS function (PMID: 25066056). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 14, 2019	PS4, PS3, PP1 -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The DHDDS p.Lys42Glu variant is known as a founder mutation in the Ashkenazi Jewish population for autosomal recessive retinitis pigmentosa (Zuchner_2011_PMID:21295283; Venturinin_2013_PMID:25255364). A case study of a family of Ashkenazi Jewish origin identified three of the four siblings with early onset retinal degeneration caused by the homozygous K42E DHDDS variant (Lam_2014_PMID:24664694). The variant was identified in dbSNP (ID: rs147394623), ClinVar (classified as pathogenic by Counsyl, Integrated Genetics and Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine) and LOVD 3.0. The variant was also identified in 63 of 282892 chromosomes at a frequency of 0.000223 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 54 of 10370 chromosomes (freq: 0.005207), Other in 3 of 7228 chromosomes (freq: 0.000415), European (non-Finnish) in 5 of 129194 chromosomes (freq: 0.000039) and Latino in 1 of 35440 chromosomes (freq: 0.000028); it was not observed in the African, East Asian, European (Finnish) and South Asian populations. Functional studies have shown altered DHDDS functional, and patients homozygous or compound heterozygous for the K42E variant were found to have significantly higher plasma and urinary dolichol profiles compared to carrier and controls; carriers of the K42E variant also had higher levels than controls suggesting an additive effect (Sabry_2016_PMID:27343064; Wen_2013_PMID:24078709). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Lys42 residue is highly conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2022	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: 28559085, 32483926, 28130426, 21295283, 24664694, 25541840, 29276052, 24078709, 28542158, 31589614, 31980526, 33413482, 32037395, 31456290, 21295282) -

Retinitis pigmentosa Pathogenic:4

Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The p.Lys42Glu variant in DHDDS was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PM3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 24, 2018	The DHDDS c.124A>G (p.Lys42Glu) missense variant has been reported in at least four studies in which it is found in a total of 35 Ashkenazi Jewish probands with retinitis pigmentosa including in 33 in a homozygous state, in one in a compound heterozygous state and in one in a heterozygous state (Zuchner et al. 2011; Zelinger et al. 2011; Wen et al. 2013; Venturini et al. 2015). When additional family members were available for testing, the p.Lys42Glu variant cosegregated with the disease in a pattern consistent with autosomal recessive inheritance, although most families assessed only included two generations (Zuchner et al. 2011; Zelinger et al. 2011). The p.Lys42Glu variant was absent from 12,870 non-Ashkenazi Jewish controls and was found in a heterozygous state in nine of 1,039 Ashkenazi Jewish controls. The variant is reported at a frequency of 0.005024 in the Ashkenazi Jewish population of the Genome Aggregation Database. Sharon et al. (2015) report the p.Lys42Glu variant to be the most common disease causing allele in the Jerusalem area with a frequency of 13.8%. The Lys42 position is conserved and affects a key residue in the active site of the enzyme. Based on the collective evidence, the p.Lys42Glu variant is classified as pathogenic for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 04, 2018	The p.Lys42Glu variant in DHDDS has been identified in the homozygous or compoun d heterozygous state in greater than 30 individuals with retinitis pigmentosa an d segregated with disease in 6 affected relatives from 4 families (Zelinger 2011 , Zuchner 2011, Venturini 2014, Kimchi 2018). This variant has also been identif ied in 0.5% (54/10370) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad. broadinstitute.org) and is thought to be a founder variant in that population. T his variant has also been reported in ClinVar (Variation ID 30709). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessi ve retinitis pigmentosa. ACMG/AMP Criteria applied: PM3_Very strong, PP1_Strong. -

Retinitis pigmentosa 59;C4693376:Developmental delay and seizures with or without movement abnormalities Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.;D;.;.;.;T;T;.;T;T;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.062	T;D;D;D;T;D;T;T;T;T;T;T;T;T
Polyphen		0.79, 1.0, 0.75	.;.;P;D;.;P;.;.;.;.;.;.;.;.
Vest4		0.63
MVP		0.61
MPC		1.6
ClinPred		0.24	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.77

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: rs147394623; hg19: chr1-26764719;