rs121909765

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_001360.3(DHCR7):c.866C>T(p.Thr289Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,770 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T289T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 8.72

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a hotspot region, there are 5 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, 0.82

PP5

Variant 11-71437909-G-A is Pathogenic according to our data. Variant chr11-71437909-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71437909-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DHCR7	NM_001360.3 linkuse as main transcript	c.866C>T	p.Thr289Ile	missense_variant	8/9	ENST00000355527.8
DHCR7	NM_001163817.2 linkuse as main transcript	c.866C>T	p.Thr289Ile	missense_variant	8/9
DHCR7	XM_011544777.3 linkuse as main transcript	c.866C>T	p.Thr289Ile	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8 linkuse as main transcript	c.866C>T	p.Thr289Ile	missense_variant	8/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251110

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461552

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000279

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000594

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 289 of the DHCR7 protein (p.Thr289Ile). This variant is present in population databases (rs121909765, gnomAD 0.004%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10995508, 11298379). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6789). 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 06, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 22, 2001	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); 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: 29300326, 11111101, 12914579, 16392899, 24500076, 11298379, 9714007, 10995508, 11186897, 11471166, 23603282, 12070263) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. Assessment of experimental evidence suggests this variant results in abnormal protein function. Elevated levels of 7-DHC were present in patients (PMID: 9714007). -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2019

The p.T289I pathogenic mutation (also known as c.866C>T), located in coding exon 6 of the DHCR7 gene, results from a C to T substitution at nucleotide position 866. The threonine at codon 289 is replaced by isoleucine, an amino acid with similar properties. This mutation has been reported in multiple individuals with Smith-Lemli-Opitz syndrome, in conjunction with a second disease-causing allele (Krakowiak PA et al. Am. J. Med. Genet., 2000 Sep;94:214-27; Nowaczyk MJ et al. Am. J. Med. Genet., 2001 Apr;100:162-3). Based on data from gnomAD, the T allele has an overall frequency of approximately 0.0016% (4/251110). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.25

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D;D;D;.

Eigen

Benign

0.024

Eigen_PC

Benign

0.050

FATHMM_MKL

Uncertain

0.94

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.82

D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.9

L;L;.;.;.

MutationTaster

Benign

0.30

A;A

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.5

D;D;D;D;N

REVEL

Pathogenic

0.70

Sift

Benign

0.037

D;D;T;T;D

Sift4G

Benign

0.16

T;T;T;D;.

Polyphen

0.68

P;P;.;.;.

Vest4

0.84

MutPred

0.63

Loss of ubiquitination at K293 (P = 0.1191);Loss of ubiquitination at K293 (P = 0.1191);.;.;.;

MVP

0.99

MPC

0.31

ClinPred

0.68

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over