ClinVar Genomic variation as it relates to human health

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.

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.

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)

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.

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.

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.

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.

PS4, PS3, PP1

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.

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).

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 59 (MIM#613861) and congenital disorder of glycosylation, type 1bb (MIM#613861); these two conditions have been lumped by ClinGen and are also referred to as congenital disorder of glycosylation (MONDO:0015286), DHDDS-related. This gene is also associated with developmental delay and seizures with or without movement abnormalities (MIM#617836), whereby missense variants are suspected to have a dominant negative effect (PMIDs: 33077723, 34382076). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants resulting in a premature termination codon and a founder missense variant within the Ashkenazi Jewish population have both been reported to cause a recessive condition (OMIM, PMID: 27343064). However, only missense variants have been reported for the dominant condition (PMID: 29100083). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (207 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0600 - Variant is located in the annotated prenyltransf domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously described as pathogenic and as a founder variant within the Ashkenazi Jewish population. The majority of individuals reported in the literature are homozygous for p.(Lys42Glu) and are diagnosed with retinal dystrophy/retinal pigmentosa (ClinVar, ClinGen). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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.

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.