rs1173707321

Positions:

• chr11-71435833-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001360.3(DHCR7):​c.970T>C​(p.Tyr324His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,450,478 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 8.12

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]

DHCR7 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity DHCR7_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 11-71435833-A-G is Pathogenic according to our data. Variant chr11-71435833-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435833-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.970T>C	p.Tyr324His	missense_variant	9/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.970T>C	p.Tyr324His	missense_variant	9/9		NP_001157289.1
DHCR7	XM_011544777.3	c.1104T>C	p.Cys368Cys	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.970T>C	p.Tyr324His	missense_variant	9/9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.385T>C	p.Tyr129His	missense_variant	8/8			ENSP00000509319.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000427 AC: 1 AN: 234444 Hom.: 0 AF XY: 0.00000774 AC XY: 1 AN XY: 129198

Gnomad AFR exome AF: 0.0000701

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1450478 Hom.: 0 Cov.: 37 AF XY: 0.00000416 AC XY: 3 AN XY: 720362

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

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: 0.00000271

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Counsyl	Sep 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 29, 2023	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 324 of the DHCR7 protein (p.Tyr324His). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (SLOS) (PMID: 10677299). ClinVar contains an entry for this variant (Variation ID: 458678). 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%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Aug 25, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.92		Loss of stability (P = 0.124);Loss of stability (P = 0.124);.;
MVP		0.98
MPC		0.53
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.97

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: rs1173707321; hg19: chr11-71146879;