NM_001360.3:c.326T>C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001360.3(DHCR7):c.326T>C(p.Leu109Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,158 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.59

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

PP5

Variant 11-71442349-A-G is Pathogenic according to our data. Variant chr11-71442349-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71442349-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3 link	c.326T>C	p.Leu109Pro	missense_variant	Exon 5 of 9	ENST00000355527.8	NP_001351.2	Q9UBM7A0A024R5F7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8 link	c.326T>C	p.Leu109Pro	missense_variant	Exon 5 of 9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320.1 link	c.-260T>C		5_prime_UTR_variant	Exon 4 of 8			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Pathogenic:4

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 109 of the DHCR7 protein (p.Leu109Pro). 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: 550951). This missense change has been observed in individuals with Smith‚ÄìLemli‚ÄìOpitz syndrome (PMID: 10677299, 10995508, 11427181, 17441222). This variant is present in population databases (rs121912195, gnomAD 0.007%). -

Inborn genetic diseases

Pathogenic:1

Apr 11, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L109P variant (also known as c.326T>C), located in coding exon 3 of the DHCR7 gene, results from a T to C substitution at nucleotide position 326. The leucine at codon 109 is replaced by proline, an amino acid with similar properties. This variant has been reported in multiple individuals with a diagnosis of Smith-Lemli-Opitz syndrome (SLOS) and second pathogenic mutation, (Witsch-Baumgartner M, Am. J. Hum. Genet. 2000 Feb; 66(2):402-12; Krakowiak PA, Am. J. Med. Genet. 2000 Sep; 94(3):214-27; Jira PE, Ann. Hum. Genet. 2001 May; 65(Pt 3):229-36; Jezela-Stanek A, J. Inherit. Metab. Dis. 2010 Dec; 33 Suppl 3:S241-8a); only one report confirmed this variant and the second pathogenic mutation to be in trans (Balogh I, Mol Syndromol 2012 Nov; 3(5):215-22). This variant was previously reported in the SNPDatabase as rs121912195. Based on data from the NHLBI Exome Sequencing Project (ESP), no alterations were observed among 12988 alleles tested (0.0%). Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. . -

not provided

Pathogenic:1

Jan 28, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15896653, 23293579, 20556518, 19390132, 22975760, 11427181, 10677299, 10995508, 12070263) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D;.;D

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.045

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.68

.;T;T;T

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

M;M;.;.

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-4.4

D;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Uncertain

0.018

D;D;.;.

Polyphen

0.99

D;D;.;.

Vest4

0.61

MutPred

0.78

Loss of stability (P = 0.1385);Loss of stability (P = 0.1385);.;Loss of stability (P = 0.1385);

MVP

0.93

MPC

0.21

ClinPred

0.85

GERP RS

2.9

Varity_R

0.76

gMVP

0.96

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