11-71441392-G-C

Variant summary

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

The NM_001360.3(DHCR7):c.461C>G(p.Thr154Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000336 in 1,613,950 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T154M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 6.92

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-71441392-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 11-71441392-G-C is Pathogenic according to our data. Variant chr11-71441392-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 166988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71441392-G-C is described in Lovd as [Pathogenic]. Variant chr11-71441392-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.461C>G	p.Thr154Arg	missense_variant	6/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.461C>G	p.Thr154Arg	missense_variant	6/9
DHCR7	XM_011544777.3	c.461C>G	p.Thr154Arg	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.461C>G	p.Thr154Arg	missense_variant	6/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000961 AC: 24 AN: 249850 Hom.: 0 AF XY: 0.0000961 AC XY: 13 AN XY: 135238

Gnomad AFR exome AF: 0.000123

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: 0.000187

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000358 AC: 524 AN: 1461718 Hom.: 0 Cov.: 34 AF XY: 0.000329 AC XY: 239 AN XY: 727164

Gnomad4 AFR exome AF: 0.000119

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: 0.0000187

Gnomad4 NFE exome AF: 0.000458

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74378

Gnomad4 AFR AF: 0.0000482

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: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000238 Hom.: 0

Bravo AF: 0.000125

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 26, 2021	Variant summary: DHCR7 c.461C>G (p.Thr154Arg) results in a non-conservative amino acid change located in the membrane-associated helix (MAH 3, Waterham_2012) of the encoded protein sequence . Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 774648 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (4e-05 vs 0.0043), allowing no conclusion about variant significance. c.461C>G has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2001, Correa-Cerro__2005, Scalco_2005, Haas_2007, Boland_2016). These data indicate that the variant is very likely to be associated with disease. Additionally, another variant at the same residue T154M has been observed in affected SLOS individuals (Witsch-Baumgartner_2001, Correa-Cerro__2005, Boland_2016), suggesting that the variant is clinically significant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 154 of the DHCR7 protein (p.Thr154Arg). This variant is present in population databases (rs143312232, gnomAD 0.02%). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 15805162, 15952211, 17237122, 20694756). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 166988). 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%. This variant disrupts the p.Thr154 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10677299, 10995508, 11427181, 15896653, 18249054, 22391996). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 09, 2021	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Apr 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 24, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 21, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 12, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 16, 2018	The DHCR7 c.461C>G (p.Thr154Arg) missense variant has been reported in at least four studies in which it is found in a total of four patients with either diagnosed or suspected Smith-Lemli-Opitz syndrome. The variant was present in three patients in a compound heterozygous state and in one patient in a heterozygous state, in whom it is not clear if a second variant was present (Witsch-Baumgartner et al. 2001; Correa-Cerro et al. 2005; Scalco et al. 2005; Haas et al. 2007). The p.Thr154Arg variant was also identified in a heterozygous state in six unaffected individuals in a large cohort undergoing routine carrier screening using next generation sequencing (Lazarin et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Thr154Arg variant is classified as likely pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2022	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: 20694756, 10995508, 10677299, 29300326, 28166604, 23042628, 15805162, 11175299, 11241839, 15670717, 12914579, 17237122, 15952211, 34426522) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.461C>G (p.T154R) alteration is located in exon 6 (coding exon 4) of the DHCR7 gene. This alteration results from a C to G substitution at nucleotide position 461, causing the threonine (T) at amino acid position 154 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the DHCR7 c.461C>G alteration was observed in 0.01% (25/281248) of total alleles studied, with a frequency of 0.02% (22/127708) in the European (non-Finnish) subpopulation. This mutation has been detected in four individuals with Smith-Lemli-Opitz syndrome (SLOS); three of the individuals carried another pathogenic mutation although the phase of these alterations was unknown (Witsch-Baumgartner, 2001; Correa-Cerro, 2005; Scalco, 2005; Haas, 2007). Based on our internal structural analysis, this mutation is predicted to be more destabilizing than nearby known pathogenic variants (Li, 2015). The p.T154R alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

DHCR7-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2023

The DHCR7 c.461C>G variant is predicted to result in the amino acid substitution p.Thr154Arg. This variant has been reported in at least three patients with Smith-Lemli-Opitz syndrome (SLOS) in addition to a second known pathogenic DHCR7 variant (Correa-Cerro et al. 2005. PubMed ID: 15805162; Scalco et al. 2005. PubMed ID: 15952211; Haas et al. 2007. PubMed ID: 17237122). It has also been reported in other SLOS patient cohorts without additional genetic segregation data included about the reported patients (Witsch-Baumgartner et al. 2001. PubMed ID: 11241839; Witsch-Baumgartner et al. 2001. PubMed ID: 11175299). A different substitution of the same amino acid (p.Thr154Met) has been reported in a number of compound heterozygous SLOS patients (Wassif et al. 2005. PubMed ID: 15896653; Jezela-Stanek et al. 2008. PubMed ID: 18249054; Roullet et al. 2012. PubMed ID: 22391996) and in an expression study using HEK293 cells, the p.Thr154Met substitution was found to lead to <5% expression (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299). The p.Thr154 amino acid is located in the third membrane-associated helix (MAH 3) of the DHCR7 protein (Waterham and Hennekam. 2012. PubMed ID: 23042628), and an internal summary of amino acid substitution prediction programs predicts the p.Thr154Arg change to be “damaging” (Liu et al. 2016. PMID: 26555599). This variant has been reported at a frequency of ~0.015% in individuals of European (Non-Finnish) origin in a large population database and has been interpreted in ClinVar as pathogenic/likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/166988/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D;D;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.8	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.97
MVP		0.96
MPC		0.60
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		1.0

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: rs143312232; hg19: chr11-71152438;