rs80338862

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000355527.8(DHCR7):ā€‹c.1228G>Cā€‹(p.Gly410Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,610,856 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 (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G410S) has been classified as Pathogenic.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 35)
Exomes š‘“: 0.000021 ( 0 hom. )

Consequence

DHCR7
ENST00000355527.8 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.89
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 1 benign, 5 uncertain in ENST00000355527.8
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-71435575-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 11-71435575-C-G is Pathogenic according to our data. Variant chr11-71435575-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1457187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null. Variant chr11-71435575-C-G is described in UniProt as null.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DHCR7NM_001360.3 linkuse as main transcriptc.1228G>C p.Gly410Arg missense_variant 9/9 ENST00000355527.8 NP_001351.2
DHCR7NM_001163817.2 linkuse as main transcriptc.1228G>C p.Gly410Arg missense_variant 9/9 NP_001157289.1
DHCR7XM_011544777.3 linkuse as main transcriptc.1362G>C p.Ser454= synonymous_variant 9/9 XP_011543079.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DHCR7ENST00000355527.8 linkuse as main transcriptc.1228G>C p.Gly410Arg missense_variant 9/91 NM_001360.3 ENSP00000347717 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
35
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
GnomAD4 exome
AF:
0.0000206
AC:
30
AN:
1458636
Hom.:
0
Cov.:
85
AF XY:
0.0000179
AC XY:
13
AN XY:
725740
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:
0.0000243
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
35
AF XY:
0.0000134
AC XY:
1
AN XY:
74368
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
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 06, 2021Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Smith-Lemli-Opitz syndrome (MIM#270400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (18 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated 4th cytoplamic loop of the transmembrane domain (PMID: 10677299). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a serine has been reported in multiple individuals with Smith-Lemli-Opitz syndrome (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in two individuals with Smith-Lemli-Opitz syndrome (PMID: 10677299, PMID: 29455191). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant reduces protein expression. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 01, 2023This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 410 of the DHCR7 protein (p.Gly410Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10677299, 29455191). ClinVar contains an entry for this variant (Variation ID: 1457187). 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.Gly410 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9653161, 12818773, 15896653). 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 02, 2022Variant summary: DHCR7 c.1228G>C (p.Gly410Arg) results in a non-conservative amino acid change in the encoded protein sequence within a transmembrane domain (Witsch-Baumgartner_2000). A known pathogenic variant affects the same nucleotide/amino acid (c.1228G>A (p.Gly410Ser), providing moderate evidence for pathogenicity. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246180 control chromosomes. c.1228G>C has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2000, Donoghue_2018), including a patient reported as compound heterozygote with a known pathogenic variant. 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
DHCR7-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 01, 2023The DHCR7 c.1228G>C variant is predicted to result in the amino acid substitution p.Gly410Arg. This variant was reported in compound heterozygosity in one patient with clinical and biochemical features consistent with Smith-Lemli-Opitz syndrome (Patient 13, Donoghue SE et al 2018. PubMed ID: 29455191). At least another patient with Smith-Lemli-Optiz syndrome has been reported with this variant. However, it is unclear if this patient was compound heterozygous for another DHCR7 variant. This variant is located in the transmembrane domain, where a large number of missense have been reported (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299). Another pathogenic substitution affecting this residue has also been reported in the literature (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299, Fitzky et al. 1998. PubMed ID: 9653161). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71146621-C-G). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.99
D;D;D
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.97
.;D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H;H;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-7.6
D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.99
MutPred
0.93
Loss of catalytic residue at G410 (P = 0.052);Loss of catalytic residue at G410 (P = 0.052);.;
MVP
0.97
MPC
0.62
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.96
gMVP
0.99

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs80338862; hg19: chr11-71146621; API