Submissions for variant NM_001360.3(DHCR7):c.862G>A (p.Glu288Lys)

gnomAD frequency: 0.00003  dbSNP: rs565893436

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000593358	SCV000706841	uncertain significance	not provided	2017-03-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000674146	SCV000799433	likely pathogenic	Smith-Lemli-Opitz syndrome	2018-04-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000674146	SCV000915550	uncertain significance	Smith-Lemli-Opitz syndrome	2018-10-05	criteria provided, single submitter	clinical testing	The DHCR7 c.862G>A (p.Glu288Lys) variant is a missense variant that has been reported in at least two clinical studies in individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al. 2001; Romano et al. 2005). Romano et al. (2005) identified the p.Glu288Lys variant in a compound heterozygous state with a second missense variant in one individual with a severe phenotype. Control data are unavailable for the p.Glu288Lys variant, which is reported at a frequency of 0.000016 in the Total population of the Genome Aggregation Database. Functional studies of this variant have not been conducted. The evidence for this variant is limited. The p.Glu288Lys variant is therefore classified as a variant of uncertain significance but suspicious for pathogenicity for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Ambry Genetics	RCV001267309	SCV001445490	uncertain significance	Inborn genetic diseases	2020-06-01	criteria provided, single submitter	clinical testing	The alteration results in an amino acid change:_x000D_ _x000D_ The c.862G>A (p.E288K) alteration is located in exon 8 (coding exon 6) of the DHCR7 gene. This alteration results from a G to A substitution at nucleotide position 862, causing the glutamic acid (E) at amino acid position 288 to be replaced by a lysine (K). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.862G>A alteration was observed in 0.0016% (4/25100) of total alleles studied. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been described from a cohort of individuals with SLOS, as well as occurring in trans with a second missense variant in one individual with a severe phenotype (Romano, 2005; Witsch-Baumgartner, 2001). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.E288 amino acid is conserved in available vertebrate species. The amino acid is located in a structurally important protein domain:_x000D_ _x000D_ The p.E288K amino acid is located in the transmembrane domain 6 (TM6) and causes changes in protein dynamics which might lead to protein dysfunction (Peng 2018). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.E288K alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000674146	SCV002293641	likely pathogenic	Smith-Lemli-Opitz syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 288 of the DHCR7 protein (p.Glu288Lys). This variant is present in population databases (rs565893436, gnomAD 0.006%). This missense change has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 16392899). ClinVar contains an entry for this variant (Variation ID: 500764). 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 DHCR7 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000674146	SCV002500087	likely pathogenic	Smith-Lemli-Opitz syndrome	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.862G>A (p.Glu288Lys) results in a conservative amino acid change located in the Transmembrane region (Peng_2018) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. A recent study using computational investigation to model the effect on protein and make predictions on SLOS phenotype based on structural and conservation properties reported this variant among Pathogenic alterations in the DHCR7 gene based on lower Relative solvent accesible surface area (rSASA), and higher evolutionary conservation (EC) compared with non-pathogenic variants (example, Peng_2018). This supports the notion of a critical amino acid residue essential for protein function. The variant allele was found at a frequency of 1.6e-05 in 251000 control chromosomes. c.862G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Smith-Lemli-Opitz Syndrome while an earlier mutational update lists this variant among mutations in patients with Smith-Lemli-Opitz Syndrome without specifying a genotype/zygosity (example, Romano_2005, Witsch-Baumgartner_2001). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29300326, 16392899, 11241839). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (LP, n=2; VUS, n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000674146	SCV005051747	likely pathogenic	Smith-Lemli-Opitz syndrome	2024-02-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000674146	SCV005629844	likely pathogenic	Smith-Lemli-Opitz syndrome	2024-06-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000674146	SCV002093022	uncertain significance	Smith-Lemli-Opitz syndrome	2019-10-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748841	SCV005360224	likely pathogenic	DHCR7-related disorder	2024-09-17	no assertion criteria provided	clinical testing	The DHCR7 c.862G>A variant is predicted to result in the amino acid substitution p.Glu288Lys. This variant has been reported in a cohort of individuals with Smith-Lemli-Opitz syndrome, though no additional information was provided on variant zygosity or patient genotype (Witsch-Baumgartner et al. 2001. PubMed ID: 11241839). It was also reported in the compound heterozygous state with a second DHCR7 variant (p.Ile251Asn) in an individual with Smith-Lemli Opitz syndrome (Romano et al. 2005. PubMed ID: 16392899). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.