ClinVar Genomic variation as it relates to human health
NM_001360.3(DHCR7):c.1349G>A (p.Arg450His)
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.
Likely pathogenic(2); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001360.3(DHCR7):c.1349G>A (p.Arg450His)
Variation ID: 558558 Accession: VCV000558558.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.4 11: 71435454 (GRCh38) [ NCBI UCSC ] 11: 71146500 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 5, 2018 Feb 14, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001360.3:c.1349G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001351.2:p.Arg450His missense NM_001163817.2:c.1349G>A NP_001157289.1:p.Arg450His missense NC_000011.10:g.71435454C>T NC_000011.9:g.71146500C>T NG_012655.2:g.17978G>A LRG_340:g.17978G>A LRG_340t1:c.1349G>A LRG_340p1:p.Arg450His - Protein change
- R450H
- Other names
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- Canonical SPDI
- NC_000011.10:71435453:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00010
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 29, 2024 | RCV000674850.15 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 2, 2020 | RCV001556929.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 24, 2017 | RCV002317913.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 15, 2023 | RCV003226367.9 |
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
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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
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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
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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. |
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Uncertain significance
(May 30, 2018)
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criteria provided, single submitter
Method: clinical testing
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Smith-Lemli-Opitz syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800251.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Smith-Lemli-Opitz syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001268262.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Likely pathogenic
(Sep 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001778601.1
First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021 |
Comment:
Identified by exome sequencing in one individual from a cohort of patients with autism, however additional clinical information on this patient was not provided and … (more)
Identified by exome sequencing in one individual from a cohort of patients with autism, however additional clinical information on this patient was not provided and variant was listed as uncertain significance (Saskin et al., 2017).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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) (less)
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Uncertain significance
(May 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000849485.4
First in ClinVar: Nov 08, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R450H variant (also known as c.1349G>A), located in coding exon 7 of the DHCR7 gene, results from a G to A substitution at nucleotide … (more)
The p.R450H variant (also known as c.1349G>A), located in coding exon 7 of the DHCR7 gene, results from a G to A substitution at nucleotide position 1349. The arginine at codon 450 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Nov 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922830.2
First in ClinVar: May 13, 2023 Last updated: Jan 06, 2024 |
Comment:
Variant summary: DHCR7 c.1349G>A (p.Arg450His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: DHCR7 c.1349G>A (p.Arg450His) 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 4e-06 in 248600 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1349G>A has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Smith-Lemli-Opitz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Smith-Lemli-Opitz syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003305469.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the DHCR7 protein (p.Arg450His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the DHCR7 protein (p.Arg450His). This variant is present in population databases (rs542266962, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Smith-Lemli-Opitz Syndrome (PMID: 10405455, 28250423). ClinVar contains an entry for this variant (Variation ID: 558558). 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.Arg450 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10405455, 15896653, 16181459, 22391996, 25405082). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. (less)
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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 |
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Prevalence of four Mendelian disorders associated with autism in 2392 affected families. | Saskin A | Journal of human genetics | 2017 | PMID: 28250423 |
Elevated Autophagy and Mitochondrial Dysfunction in the Smith-Lemli-Opitz Syndrome. | Chang S | Molecular genetics and metabolism reports | 2014 | PMID: 25405082 |
No evidence for mevalonate shunting in moderately affected children with Smith-Lemli-Opitz syndrome. | Roullet JB | Journal of inherited metabolic disease | 2012 | PMID: 22391996 |
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 |
Biochemical variants of Smith-Lemli-Opitz syndrome. | Neklason DW | American journal of medical genetics | 1999 | PMID: 10405455 |
Text-mined citations for rs542266962 ...
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.