rs565893436

chr11-71437913-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001360.3(DHCR7):c.862G>A(p.Glu288Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 6.89

Genes affected

DHCR7 (HGNC:2860): (7-dehydrocholesterol reductase) This gene encodes an enzyme that removes the C(7-8) double bond in the B ring of sterols and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. This gene is ubiquitously expressed and its transmembrane protein localizes to the endoplasmic reticulum membrane and nuclear outer membrane. Mutations in this gene cause Smith-Lemli-Opitz syndrome (SLOS); a syndrome that is metabolically characterized by reduced serum cholesterol levels and elevated serum 7-dehydrocholesterol levels and phenotypically characterized by cognitive disability, facial dysmorphism, syndactyly of second and third toes, and holoprosencephaly in severe cases to minimal physical abnormalities and near-normal intelligence in mild cases. Alternative splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 11-71437913-C-T is Pathogenic according to our data. Variant chr11-71437913-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 500764.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3}. Variant chr11-71437913-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.862G>A	p.Glu288Lys	missense_variant	8/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.862G>A	p.Glu288Lys	missense_variant	8/9
DHCR7	XM_011544777.3	c.862G>A	p.Glu288Lys	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.862G>A	p.Glu288Lys	missense_variant	8/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152192 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251000 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461496 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 727054

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152310 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:3 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 20, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 05, 2018	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 10, 2019	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2020

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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	4.3	H;H;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;D;.;.;.
Vest4		1.0
MutPred		0.92		Gain of methylation at E288 (P = 0.0115);Gain of methylation at E288 (P = 0.0115);.;.;.;
MVP		0.99
MPC		0.61
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		1.0

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: rs565893436; hg19: chr11-71148959; COSMIC: COSV62794728; COSMIC: COSV62794728;