rs200334114

Variant names:

• chr11-71444864-C-G
• rs200334114
• NM_001360.3:c.89G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-71444864-C-G
• chr11-71444864-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM5 PP3 PP5

The NM_001360.3(DHCR7):​c.89G>C​(p.Gly30Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,614,062 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G30S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:2
• Conservation: PhyloP100: 3.75
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Smith-Lemli-Opitz syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001360.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-71444865-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1934663.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754
• PP5: Variant 11-71444864-C-G is Pathogenic according to our data. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518. Variant chr11-71444864-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 397518.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.89G>C	p.Gly30Ala	missense_variant	Exon 3 of 9	ENST00000355527.8	NP_001351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.89G>C	p.Gly30Ala	missense_variant	Exon 3 of 9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.-333-803G>C		intron_variant	Intron 2 of 7			ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152242 Hom.: 0 Cov.: 33

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000636 AC: 16 AN: 251494 AF XY: 0.0000662

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.000129 AC XY: 94 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000166 AC: 185 AN: 1111842

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:6 Uncertain:1

Sep 14, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This heterozygous missense variant in the DHCR7 gene (autosomal recessive transmission) inherited from the mother was found to be present in combination with a second missense variant in the same gene (compound heterozygosity) in a young female patient with a severe form of ASD -

Jun 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 30 of the DHCR7 protein (p.Gly30Ala). This variant is present in population databases (rs200334114, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of DHCR7-related conditions (PMID: 17497248, 17994283, 34958143). ClinVar contains an entry for this variant (Variation ID: 397518). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DHCR7 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Mar 21, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DHCR7 c.89G>C (p.Gly30Ala) results in a non-conservative amino acid change in 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 6.4e-05 in 251594 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (6.4e-05 vs 0.0043), allowing no conclusion about variant significance. c.89G>C has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome (Blahakova_2007, Haas_2007, Gabriel_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23042628, 17497248, 17994283, 34958143). ClinVar contains an entry for this variant (Variation ID: 397518). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Feb 21, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

-

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3 Uncertain:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DHCR7: PM3:Very Strong, PM2 -

Nov 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 28250423, 23042628, 17497248, 34958143, 34308104, 17994283, 27535533) -

Jul 25, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PM2, PM3_strong -

Inborn genetic diseases Pathogenic:1

Apr 03, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.89G>C (p.G30A) alteration is located in exon 3 (coding exon 1) of the DHCR7 gene. This alteration results from a G to C substitution at nucleotide position 89, causing the glycine (G) at amino acid position 30 to be replaced by an alanine (A). Based on data from gnomAD, the C allele has an overall frequency of 0.006% (18/282898) total alleles studied. The highest observed frequency was 0.014% (18/129194) of European (non-Finnish) alleles. This variant has been identified in conjunction with another DHCR7 variant in one individual with Smith-Lemli-Opitz confirmed by sterol analysis, in one individual with corpus callosum agenesis and ventriculomegaly, and in the fetus of one pregnant individual with increased 7-DHCR in amniotic fluid (Haas, 2007; Blahakova, 2007; Gabriel, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

DHCR7-related disorder Pathogenic:1

May 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DHCR7 c.89G>C variant is predicted to result in the amino acid substitution p.Gly30Ala. This variant has been reported, along with a second causative variant, in two patients with biochemically diagnosed Smith-Lemli-Opitz syndrome (SLOS) (Haas et al. 2007. PubMed ID: 17497248). It has also been observed along with a second causative variant in a prenatal case with biochemical test results consistent with SLOS (i.e. elevated 7-dehydrocholesterol in the amniotic fluid) (Blahakova et al. 2007. PubMed ID: 17994283). In addition, the c.89G>C variant was identified, along with a nonsense variant in DHCR7 gene, in a fetus with corpus callosum agenesis, and ventriculomegaly (Table S1, Gabriel et al. 2022. PubMed ID: 34958143). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71155910-C-G). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.;T;T;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;T;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.;.
PhyloP100		3.7
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.027	D;D;T;D;D;D;D
Sift4G	Uncertain	0.028	D;D;.;.;T;.;T
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.80
MVP		0.94
MPC		0.59
ClinPred		0.92	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.84
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs200334114; hg19: chr11-71155910; COSMIC: COSV106107973; COSMIC: COSV106107973;