ClinVar Genomic variation as it relates to human health
NM_001360.3(DHCR7):c.1337G>A (p.Arg446Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001360.3(DHCR7):c.1337G>A (p.Arg446Gln)
Variation ID: 431994 Accession: VCV000431994.58
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.4 11: 71435466 (GRCh38) [ NCBI UCSC ] 11: 71146512 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 20, 2017 Feb 20, 2024 Jan 10, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001360.3:c.1337G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001351.2:p.Arg446Gln missense NM_001163817.2:c.1337G>A NP_001157289.1:p.Arg446Gln missense NC_000011.10:g.71435466C>T NC_000011.9:g.71146512C>T NG_012655.2:g.17966G>A LRG_340:g.17966G>A LRG_340t1:c.1337G>A LRG_340p1:p.Arg446Gln - Protein change
- R446Q
- Other names
- -
- Canonical SPDI
- NC_000011.10:71435465:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
DHCR7 | - | - |
GRCh38 GRCh37 |
912 | 927 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 19, 2018 | RCV000498273.11 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2024 | RCV000576656.25 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 27, 2017 | RCV002311810.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Oct 23, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Smith-Lemli-Opitz syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000677989.1
First in ClinVar: Jan 07, 2018 Last updated: Jan 07, 2018 |
|
|
Pathogenic
(Jun 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000854975.1
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Pathogenic
(Nov 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589633.2
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Comment:
The R446Q missense variant has been reported previously in several unrelated individuals with SLOSwho also harbored a second variant in the DHCR7 gene (Ginat et … (more)
The R446Q missense variant has been reported previously in several unrelated individuals with SLOSwho also harbored a second variant in the DHCR7 gene (Ginat et al., 2004; Witsch-Baumgartner et al.,2005; Jezela-Stanek et al., 2010). The R446Q variant is not observed at a significant frequency inlarge population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome VariantServer). The R446Q variant is a semi-conservative amino acid substitution, which may impactsecondary protein structure as these residues differ in some properties. This substitution occurs at aposition that is conserved across species. In silico analysis predicts this variant is probably damaging tothe protein structure/function. Additionally, in silico analysis predicts that the c.1337 G>A variantresponsible for R446Q creates a new cryptic slice acceptor site in exon 9, downstream of the naturalsplice acceptor site in intron 8. However, in the absence of RNA/functional studies, the actual effectof this sequence change in this individual is unknown. In summary, we interpret R446Q as pathogenic. (less)
|
|
Pathogenic
(Aug 20, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Smith-Lemli-Opitz syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917277.1
First in ClinVar: May 31, 2019 Last updated: May 31, 2019 |
Comment:
Variant summary: DHCR7 c.1337G>A (p.Arg446Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: DHCR7 c.1337G>A (p.Arg446Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 274922 control chromosomes (gnomAD). c.1337G>A has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (e.g. Witsch-Baumgartner 2000, Ciara 2004, Sparks 2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Ginat 2004). The most pronounced variant effect results in <10% of normal activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Smith-Lemli-Opitz syndrome
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163680.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
|
|
Pathogenic
(Dec 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Smith-Lemli-Opitz syndrome
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512348.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4 moderate, PM2 moderate, PM2, PM3 very strong, PP1 supporting, PP1, PP3 supporting
Geographic origin: Brazil
|
|
Likely pathogenic
(Oct 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000847101.4
First in ClinVar: Nov 08, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R446Q variant (also known as c.1337G>A), located in coding exon 7 of the DHCR7 gene, results from a G to A substitution at nucleotide … (more)
The p.R446Q variant (also known as c.1337G>A), located in coding exon 7 of the DHCR7 gene, results from a G to A substitution at nucleotide position 1337. The arginine at codon 446 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in conjunction with a second DHCR7 alteration in at least five individuals with clinically and biochemically confirmed diagnoses of Smith-Lemli-Opitz syndrome (SLOS) (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Jezela-Stanek A et al. Eur J Med Genet Dec;51:124-40; Patrono C et al. Mol. Cell. Probes, 2002 Aug;16:315-8; Ciara E et al. Clin. Genet., 2004 Dec;66:517-24). 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. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Apr 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Smith-Lemli-Opitz syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893236.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Smith-Lemli-Opitz syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000930805.7
First in ClinVar: Aug 13, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 446 of the DHCR7 protein (p.Arg446Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 446 of the DHCR7 protein (p.Arg446Gln). This variant is present in population databases (rs751604696, gnomAD 0.006%). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 10677299, 12270273, 12818773, 15521979, 27513191). 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: 431994). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. | Wassif CA | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27513191 |
Characterization of large deletions in the DHCR7 gene. | Lanthaler B | Clinical genetics | 2015 | PMID: 25040602 |
Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome. | Sparks SE | Journal of inherited metabolic disease | 2014 | PMID: 24500076 |
Mild Smith-Lemli-Opitz syndrome: further delineation of 5 Polish cases and review of the literature. | Jezela-Stanek A | European journal of medical genetics | 2008 | PMID: 18249054 |
Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol. | Pappu AS | Journal of lipid research | 2006 | PMID: 16983147 |
Identification of 14 novel mutations in DHCR7 causing the Smith-Lemli-Opitz syndrome and delineation of the DHCR7 mutational spectra in Spain and Italy. | Witsch-Baumgartner M | Human mutation | 2005 | PMID: 15776424 |
DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome. | Ciara E | Clinical genetics | 2004 | PMID: 15521979 |
Lowered DHCR7 activity measured by ergosterol conversion in multiple cell types in Smith-Lemli-Opitz syndrome. | Ginat S | Molecular genetics and metabolism | 2004 | PMID: 15464432 |
[Clinical characteristics and diagnosis of Smith-Lemli-Opitz syndrome and tentative phenotype-genotype correlation: report of 45 cases]. | Goldenberg A | Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | 2003 | PMID: 12818773 |
Two novel mutations of the human delta7-sterol reductase (DHCR7) gene in children with Smith-Lemli-Opitz syndrome. | Patrono C | Molecular and cellular probes | 2002 | PMID: 12270273 |
Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations. | Witsch-Baumgartner M | European journal of human genetics : EJHG | 2001 | PMID: 11175299 |
Smith-Lemli-Opitz syndrome: molecular-genetic analysis of ten families. | Kozák L | Journal of inherited metabolic disease | 2000 | PMID: 10896306 |
Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. | Witsch-Baumgartner M | American journal of human genetics | 2000 | PMID: 10677299 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DHCR7 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs751604696 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.