Has not been previously published as pathogenic or benign to our knowledge; However, a different variant (c.1349G>T) resulting in the same missense alteration (p.R450L) have been reported in association with Smith-Lemli-Optiz syndrome (Witsch-Baumgartner et al., 2000; Correra-Cerro et al., 2005); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 10677299, 16181459, 15805162, 10405455)
ClinVar Genomic variation as it relates to human health
NM_001360.3(DHCR7):c.1349_1350delinsTG (p.Arg450Leu)
Germline
Classification
Help
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.
(5)
Help
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.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001360.3(DHCR7):c.1349_1350delinsTG (p.Arg450Leu)
Variation ID: 652894 Accession: VCV000652894.29
- Type and length
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Indel, 2 bp
- Location
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Cytogenetic: 11q13.4 11: 71435453-71435454 (GRCh38) [ NCBI UCSC ] 11: 71146499-71146500 (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 14, 2019 Oct 20, 2024 May 29, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001360.3:c.1349_1350delinsTG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001351.2:p.Arg450Leu missense NM_001163817.2:c.1349_1350delinsTG NP_001157289.1:p.Arg450Leu missense NM_001360.2:c.1349_1350delGCinsTG NC_000011.10:g.71435453_71435454delinsCA NC_000011.9:g.71146499_71146500delinsCA NG_012655.2:g.17978_17979delinsTG LRG_340:g.17978_17979delinsTG LRG_340t1:c.1349_1350delinsTG LRG_340p1:p.Arg450Leu - Protein change
- R450L
- Other names
- -
- Canonical SPDI
- NC_000011.10:71435452:GC:CA
-
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.
- -
- Links
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 |
937 | 952 | |
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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 29, 2024 | RCV000808556.13 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 1, 2023 | RCV001560504.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 28, 2020 | RCV002381791.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001782932.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Has not been previously published as pathogenic or benign to our knowledge; However, a different variant (c.1349G>T) resulting in the same missense alteration (p.R450L) have … (more)
Has not been previously published as pathogenic or benign to our knowledge; However, a different variant (c.1349G>T) resulting in the same missense alteration (p.R450L) have been reported in association with Smith-Lemli-Optiz syndrome (Witsch-Baumgartner et al., 2000; Correra-Cerro et al., 2005); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 10677299, 16181459, 15805162, 10405455) (less)
|
|
|
Pathogenic
(Oct 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Smith-Lemli-Opitz syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000948666.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 450 of the DHCR7 protein (p.Arg450Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 450 of the DHCR7 protein (p.Arg450Leu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10405455, 15896653, 16181459, 22391996, 25405082). ClinVar contains an entry for this variant (Variation ID: 652894). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 9714006, 10405455, 10677299). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jul 28, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002690293.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1349_1350delGCinsTG pathogenic mutation, located in coding exon 7 of the DHCR7 gene, results from an in-frame deletion of GC and insertion of TG at … (more)
The c.1349_1350delGCinsTG pathogenic mutation, located in coding exon 7 of the DHCR7 gene, results from an in-frame deletion of GC and insertion of TG at nucleotide positions 1349 to 1350. This results in the substitution of the arginine residue for a leucine residue at codon 450, an amino acid with dissimilar properties. This alteration has been detected in conjunction with other known pathogenic mutations in DHCR7 (c.964-1G>C, p.R242C, p.Q95*/p.Q98*) in several individuals with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Correa-Cerro LS et al. Mol. Genet. Metab., 2005 Feb;84:112-26; Wassif CA et al. Genet. Med., 2017 03;19:297-305; Chang S et al. Mol Genet Metab Rep, 2014;1:431-442; Anstey AV et al. Br. J. Dermatol., 2005 Oct;153:774-9; Bianconi SE et al. Am. J. Med. Genet. A, 2011 Nov;155A:2732-8; Eroglu Y et al. Am. J. Med. Genet. A, 2017 Aug;173:2097-2100). In addition, several functional studies showed that this alteration resulted in significantly reduced enzymatic activity when expressed in cell lines (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Correa-Cerro LS et al. Mol. Genet. Metab., 2005 Feb;84:112-26; Wassif CA et al. Genet. Med., 2017 03;19:297-305). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Likely pathogenic
(May 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Smith-Lemli-Opitz syndrome
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV005200832.1
First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024 |
Comment:
PS1, PM2, PM3_Supporting
|
|
|
Pathogenic
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004010100.12
First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024 |
Comment:
DHCR7: PS1, PM2, PM3, PP4, PS3:Supporting
Number of individuals with the variant: 4
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 450 of the DHCR7 protein (p.Arg450Leu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10405455, 15896653, 16181459, 22391996, 25405082). ClinVar contains an entry for this variant (Variation ID: 652894). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 9714006, 10405455, 10677299). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1349_1350delGCinsTG pathogenic mutation, located in coding exon 7 of the DHCR7 gene, results from an in-frame deletion of GC and insertion of TG at nucleotide positions 1349 to 1350. This results in the substitution of the arginine residue for a leucine residue at codon 450, an amino acid with dissimilar properties. This alteration has been detected in conjunction with other known pathogenic mutations in DHCR7 (c.964-1G>C, p.R242C, p.Q95*/p.Q98*) in several individuals with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Correa-Cerro LS et al. Mol. Genet. Metab., 2005 Feb;84:112-26; Wassif CA et al. Genet. Med., 2017 03;19:297-305; Chang S et al. Mol Genet Metab Rep, 2014;1:431-442; Anstey AV et al. Br. J. Dermatol., 2005 Oct;153:774-9; Bianconi SE et al. Am. J. Med. Genet. A, 2011 Nov;155A:2732-8; Eroglu Y et al. Am. J. Med. Genet. A, 2017 Aug;173:2097-2100). In addition, several functional studies showed that this alteration resulted in significantly reduced enzymatic activity when expressed in cell lines (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Correa-Cerro LS et al. Mol. Genet. Metab., 2005 Feb;84:112-26; Wassif CA et al. Genet. Med., 2017 03;19:297-305). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
PS1, PM2, PM3_Supporting
Comment:
DHCR7: PS1, PM2, PM3, PP4, PS3:Supporting
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. |
Comment:
Has not been previously published as pathogenic or benign to our knowledge; However, a different variant (c.1349G>T) resulting in the same missense alteration (p.R450L) have been reported in association with Smith-Lemli-Optiz syndrome (Witsch-Baumgartner et al., 2000; Correra-Cerro et al., 2005); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 10677299, 16181459, 15805162, 10405455)
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 450 of the DHCR7 protein (p.Arg450Leu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10405455, 15896653, 16181459, 22391996, 25405082). ClinVar contains an entry for this variant (Variation ID: 652894). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 9714006, 10405455, 10677299). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1349_1350delGCinsTG pathogenic mutation, located in coding exon 7 of the DHCR7 gene, results from an in-frame deletion of GC and insertion of TG at nucleotide positions 1349 to 1350. This results in the substitution of the arginine residue for a leucine residue at codon 450, an amino acid with dissimilar properties. This alteration has been detected in conjunction with other known pathogenic mutations in DHCR7 (c.964-1G>C, p.R242C, p.Q95*/p.Q98*) in several individuals with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Correa-Cerro LS et al. Mol. Genet. Metab., 2005 Feb;84:112-26; Wassif CA et al. Genet. Med., 2017 03;19:297-305; Chang S et al. Mol Genet Metab Rep, 2014;1:431-442; Anstey AV et al. Br. J. Dermatol., 2005 Oct;153:774-9; Bianconi SE et al. Am. J. Med. Genet. A, 2011 Nov;155A:2732-8; Eroglu Y et al. Am. J. Med. Genet. A, 2017 Aug;173:2097-2100). In addition, several functional studies showed that this alteration resulted in significantly reduced enzymatic activity when expressed in cell lines (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Correa-Cerro LS et al. Mol. Genet. Metab., 2005 Feb;84:112-26; Wassif CA et al. Genet. Med., 2017 03;19:297-305). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
PS1, PM2, PM3_Supporting
Comment:
DHCR7: PS1, PM2, PM3, PP4, PS3:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Normal IQ is possible in Smith-Lemli-Opitz syndrome. | Eroglu Y | American journal of medical genetics. Part A | 2017 | PMID: 28349652 |
| 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 |
| Elevated Autophagy and Mitochondrial Dysfunction in the Smith-Lemli-Opitz Syndrome. | Chang S | Molecular genetics and metabolism reports | 2014 | PMID: 25405082 |
| Mutational spectrum of Smith-Lemli-Opitz syndrome. | Waterham HR | American journal of medical genetics. Part C, Seminars in medical genetics | 2012 | PMID: 23042628 |
| No evidence for mevalonate shunting in moderately affected children with Smith-Lemli-Opitz syndrome. | Roullet JB | Journal of inherited metabolic disease | 2012 | PMID: 22391996 |
| Adrenal function in Smith-Lemli-Opitz syndrome. | Bianconi SE | American journal of medical genetics. Part A | 2011 | PMID: 21990131 |
| Photosensitive Smith-Lemli-Opitz syndrome is not caused by a single gene mutation: analysis of the gene encoding 7-dehydrocholesterol reductase in five U.K. families. | Anstey AV | The British journal of dermatology | 2005 | PMID: 16181459 |
| Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith-Lemli-Opitz syndrome fibroblasts. | Wassif CA | Molecular genetics and metabolism | 2005 | PMID: 15896653 |
| DHCR7 nonsense mutations and characterisation of mRNA nonsense mediated decay in Smith-Lemli-Opitz syndrome. | Correa-Cerro LS | Journal of medical genetics | 2005 | PMID: 15805162 |
| 3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome. | Correa-Cerro LS | Molecular genetics and metabolism | 2005 | PMID: 15670717 |
| Mutations in the human DHCR7 gene. | Witsch-Baumgartner M | Human mutation | 2001 | PMID: 11241839 |
| 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 |
| Biochemical variants of Smith-Lemli-Opitz syndrome. | Neklason DW | American journal of medical genetics | 1999 | PMID: 10405455 |
| Variant RSH/Smith-Lemli-Opitz syndrome with atypical sterol metabolism. | Anderson AJ | American journal of medical genetics | 1998 | PMID: 9714006 |
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Text-mined citations for rs1591107040 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.