rs121909766

Positions:

• chr11-71437936-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000355527.8(DHCR7):​c.839A>G​(p.Tyr280Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y280D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: DHCR7 ENST00000355527.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.99

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000355527.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-71437937-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2854167.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 11-71437936-T-C is Pathogenic according to our data. Variant chr11-71437936-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71437936-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.839A>G	p.Tyr280Cys	missense_variant	8/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.839A>G	p.Tyr280Cys	missense_variant	8/9		NP_001157289.1
DHCR7	XM_011544777.3	c.839A>G	p.Tyr280Cys	missense_variant	8/9		XP_011543079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.839A>G	p.Tyr280Cys	missense_variant	8/9	1	NM_001360.3	ENSP00000347717	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 15, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2022	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 6790). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 11857552). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 280 of the DHCR7 protein (p.Tyr280Cys). -

DHCR7-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2023

The DHCR7 c.839A>G variant is predicted to result in the amino acid substitution p.Tyr280Cys. This variant was reported in the compound heterozygous state with a known pathogenic DHCR7 variant (c.964-1G>C) in an individual with Smith-Lemli-Opitz syndrome (SLOS) (Prasad et al. 2002. PubMed ID: 11857552). It was also reported in a study of Canadian SLOS patients, though no additional functional or genetic evidence was provided that could help clarify pathogenicity of the variant (Waye et al. 2002. PubMed ID: 12070263). The p.Tyr280 amino acid is located in a transmembrane domain (Nowaczyk. 2001. PubMed ID: 11453964) and suspected to be disruptive to the DHCR7 protein (Prasad et al. 2002. PubMed ID: 11857552). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Taken together, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-8.5	D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.99
MutPred		0.91		Loss of catalytic residue at I279 (P = 0.0645);Loss of catalytic residue at I279 (P = 0.0645);.;.;.;
MVP		1.0
MPC		0.64
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99

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: rs121909766; hg19: chr11-71148982;