rs121912195

Positions:

• chr11-71442349-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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 (★★). Synonymous variant affecting the same amino acid position (i.e. L109L) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.59

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 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/exons	MANE	UniProt
DHCR7	NM_001360.3	c.326T>C	p.Leu109Pro	missense_variant	5/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.326T>C	p.Leu109Pro	missense_variant	5/9
DHCR7	XM_011544777.3	c.326T>C	p.Leu109Pro	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.326T>C	p.Leu109Pro	missense_variant	5/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32

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.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74312

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.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 25, 2023	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–Lemli–Opitz syndrome (PMID: 10677299, 10995508, 11427181, 17441222). This variant is present in population databases (rs121912195, gnomAD 0.007%). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 14, 2017	- -
Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2016

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2020

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	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	23
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	D
LIST_S2	Benign	0.68	.;T;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.40	T
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	D
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

Other links and lift over

dbSNP: rs121912195; hg19: chr11-71153395;