rs773134475
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_001360.3(DHCR7):c.1190C>T(p.Ser397Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,609,556 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 0.0000066 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
DHCR7
NM_001360.3 missense
NM_001360.3 missense
Scores
9
3
4
Clinical Significance
Conservation
PhyloP100: 8.72
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.759
PP5
Variant 11-71435613-G-A is Pathogenic according to our data. Variant chr11-71435613-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 587952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435613-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.1190C>T | p.Ser397Leu | missense_variant | 9/9 | ENST00000355527.8 | NP_001351.2 | |
DHCR7 | NM_001163817.2 | c.1190C>T | p.Ser397Leu | missense_variant | 9/9 | NP_001157289.1 | ||
DHCR7 | XM_011544777.3 | c.1324C>T | p.Arg442Trp | missense_variant | 9/9 | XP_011543079.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.1190C>T | p.Ser397Leu | missense_variant | 9/9 | 1 | NM_001360.3 | ENSP00000347717 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 35
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GnomAD3 exomes AF: 0.0000124 AC: 3AN: 241462Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132186
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GnomAD4 exome AF: 0.0000137 AC: 20AN: 1457328Hom.: 0 Cov.: 85 AF XY: 0.0000165 AC XY: 12AN XY: 725202
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1AN XY: 74372
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 08, 2021 | Variant summary: DHCR7 c.1190C>T (p.Ser397Leu) results in a non-conservative amino acid change located in the fourth cytoplasmic loop domain 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 1.2e-05 in 241462 control chromosomes. c.1190C>T has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome and subsequently cited by others (example, Witsch-Baumgartner_2000, Ciara_2004, Kalb_2012, Balogh_2012, Donoghue_2018). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000587952). The variant has been reported to be in trans with pathogenic variant(s) as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 15521979, 22211794, 23293579). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 08, 2023 | This missense change has been observed in individual(s) with Smith-Lemli-Opitz Syndrome (PMID: 10677299, 15521979, 22211794, 23293579). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs773134475, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 397 of the DHCR7 protein (p.Ser397Leu). ClinVar contains an entry for this variant (Variation ID: 587952). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 17, 2022 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 20, 2016 | The p.S397L variant (also known as c.1190C>T), located in coding exon 7 of the DHCR7 gene, results from a C to T substitution at nucleotide position 1190. The serine at codon 397 is replaced by leucine, an amino acid with dissimilar properties. This variant was identified in multiple patients with Smith-Lemli-Opitz Syndrome, who also carried pathogenic mutations in DHCR7 (Witsch-Baumgartner M et al, Am. J. Hum. Genet. 2000 Feb; 66(2):402-12; Ciara E et al, Clin. Genet. 2004 Dec; 66(6):517-24; Balogh I et al, Mol Syndromol 2012 Nov; 3(5):215-22; Kalb S et al, Clin. Genet. 2012 Jun; 81(6):598-601). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6487 samples (12974 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
MutPred
Gain of catalytic residue at R231 (P = 0.0361);
MVP
ClinPred
D
GERP RS
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at