ClinVar Genomic variation as it relates to human health
NM_001360.3(DHCR7):c.724C>T (p.Arg242Cys)
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
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NM_001360.3(DHCR7):c.724C>T (p.Arg242Cys)
Variation ID: 21275 Accession: VCV000021275.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.4 11: 71438986 (GRCh38) [ NCBI UCSC ] 11: 71150032 (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 Apr 4, 2013 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001360.3:c.724C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001351.2:p.Arg242Cys missense NM_001163817.2:c.724C>T NP_001157289.1:p.Arg242Cys missense NC_000011.10:g.71438986G>A NC_000011.9:g.71150032G>A NG_012655.2:g.14446C>T LRG_340:g.14446C>T LRG_340t1:c.724C>T LRG_340p1:p.Arg242Cys Q9UBM7:p.Arg242Cys - Protein change
- R242C
- Other names
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- Canonical SPDI
- NC_000011.10:71438985:G:A
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00010
The Genome Aggregation Database (gnomAD) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00016
Exome Aggregation Consortium (ExAC) 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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. |
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DHCR7 | - | - |
GRCh38 GRCh37 |
917 | 932 |
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
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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
Help
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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 24, 2023 | RCV000389331.9 | |
Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000020438.30 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 19, 2021 | RCV002371778.2 |
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
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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
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. |
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Pathogenic
(Sep 08, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331535.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Apr 27, 2017)
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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: SCV000373917.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
Across a selection of available literature, the DHCR7 c.724C>T (p.Arg242Cys) missense variant has been identified in a compound heterozygous state in at least six individuals … (more)
Across a selection of available literature, the DHCR7 c.724C>T (p.Arg242Cys) missense variant has been identified in a compound heterozygous state in at least six individuals with Smith-Lemli-Opitz syndrome and in two additional patients with unknown zygosity (Neklason et al. 1999; Krakowiak et al. 2000; Witsch-Baumgartner et al. 2000; Waye et al. 2005; Tucci et al. 2016). In a review, Boland et al. (2016) report that the p.Arg242Cys variant was found in 12 out of 1037 (1.2%) patient alleles across 30 studies. The p.Arg242Cys variant was absent from 50 controls and is reported at a frequency of 0.00029 in the African population of the Exome Aggregation. Functional studies demonstrated that the enzymatic activity in fibroblasts derived from a patient who was compound heterozygous for the p.Arg242Cys variant and another missense variant was significantly reduced (Ginat et al. 2004). Based on the evidence, the p.Arg242Cys variant is classified as pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Sep 11, 2015)
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criteria provided, single submitter
Method: clinical testing
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Smith-Lemli-Opitz syndrome
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711726.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Arg242Cys (NM_000060.2 c.724C>T) variant in DHCR7 has been reported in at least 6 individuals with clinical features of Smith-Lemli-Opitz syndrome who wer e compound … (more)
The p.Arg242Cys (NM_000060.2 c.724C>T) variant in DHCR7 has been reported in at least 6 individuals with clinical features of Smith-Lemli-Opitz syndrome who wer e compound heterozygotes for a second DHCR7 variant, and segregated with disease in one affected family member (Neklason 1999, Krakowiak 2000, Waye 2002, Correa -Cerro 2005, Waye 2005, Tucci 2016). This variant has also been identified in 19 /126,670 of European chromosomes by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs80338856). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. In vitro functional studies provide some evide nce that the p.Arg242Cys variant may impact protein function (Neklason 1999). In summary, although additional studies are required to fully establish its clinic al significance, the p.Arg242Cys variant is likely pathogenic for Smith-Lemli-Op itz syndrome in an autosomal recessive manner based on its occurrence in affecte d individuals, low frequency in controls, and functional data. (less)
Number of individuals with the variant: 4
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Pathogenic
(-)
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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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Baylor Genetics
Accession: SCV001163328.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Likely pathogenic
(Dec 04, 2019)
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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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Myriad Genetics, Inc.
Accession: SCV001193935.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_001360.2(DHCR7):c.724C>T(R242C) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 10677299, 15954111, 10995508, 18076100, 10405455, … (more)
NM_001360.2(DHCR7):c.724C>T(R242C) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 10677299, 15954111, 10995508, 18076100, 10405455, and 16983147. Classification of NM_001360.2(DHCR7):c.724C>T(R242C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Feb 24, 2023)
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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: SCV000329334.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 26, 2023 |
Comment:
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: 26969503, … (more)
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: 26969503, 22975760, 28166604, 27415407, 11175299, 10677299, 16207203, 12070263, 10405455, 10995508, 27401223, 23042628, 15464432, 15954111, 28250423, 30609409, 31589614, 34308104) (less)
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Pathogenic
(Sep 06, 2019)
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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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Revvity Omics, Revvity
Accession: SCV002020376.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 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: SCV000825551.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 242 of the DHCR7 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 242 of the DHCR7 protein (p.Arg242Cys). This variant is present in population databases (rs80338856, gnomAD 0.02%). This missense change has been observed in individuals with Smith-Lemli-Opitz syndrome (PMID: 10405455, 10677299, 10995508, 15464432, 15954111, 26969503). ClinVar contains an entry for this variant (Variation ID: 21275). 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%. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 15464432). This variant disrupts the p.Arg242 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10995508, 11427181, 12818773, 15776424, 16044199). 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. (less)
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Pathogenic
(Aug 19, 2021)
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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: SCV002670250.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.724C>T (p.R242C) alteration is located in exon 7 (coding exon 5) of the DHCR7 gene. This alteration results from a C to T substitution … (more)
The c.724C>T (p.R242C) alteration is located in exon 7 (coding exon 5) of the DHCR7 gene. This alteration results from a C to T substitution at nucleotide position 724, causing the arginine (R) at amino acid position 242 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (27/282746) total alleles studied. The highest observed frequency was 0.02% (4/24962) of African alleles. This mutation was identified in multiple individuals with Smith-Lemli-Opitz syndrome (SLOS) (Neklason, 1999; Krakowiak, 2000; Ginat, 2004; Waye, 2005; Tucci, 2016; Saskin, 2017). This amino acid position is highly conserved in available vertebrate species. Enzyme activity in a cell line from an individual with SLOS with this mutation demonstrated reduced activity (Ginat, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Aug 04, 2016)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697848.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Variant summary: The DHCR7 c.724C>T (p.Arg242Cys) variant located in the transmembrane domain causes a missense change involving a conserved nucleotide with 5/5 in silico tools … (more)
Variant summary: The DHCR7 c.724C>T (p.Arg242Cys) variant located in the transmembrane domain causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 10/121036 (1/12106), which does not exceed the maximal expected allele frequency for a pathogenic DHCR7 variant of 1/230. The variant of interest has been reported in multiple affected individuals via publications. In addition, GeneReviews cites the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. (less)
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Pathogenic
(Oct 31, 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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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893242.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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not provided
(-)
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no classification provided
Method: literature only
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Smith-Lemli-Opitz syndrome
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000040852.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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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Smith-Lemli-Opitz Syndrome. | Adam MP | - | 2020 | PMID: 20301322 |
Prevalence of four Mendelian disorders associated with autism in 2392 affected families. | Saskin A | Journal of human genetics | 2017 | PMID: 28250423 |
Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review. | Boland MR | The pharmacogenomics journal | 2016 | PMID: 27401223 |
The p.Phe174Ser mutation is associated with mild forms of Smith Lemli Opitz Syndrome. | Tucci A | BMC medical genetics | 2016 | PMID: 26969503 |
Acute postnatal cataract formation in Smith-Lemli-Opitz syndrome. | Goodwin H | American journal of medical genetics. Part A | 2008 | PMID: 18076100 |
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 |
Recent insights into the Smith-Lemli-Opitz syndrome. | Yu H | Clinical genetics | 2005 | PMID: 16207203 |
R352Q mutation of the DHCR7 gene is common among Japanese Smith-Lemli-Opitz syndrome patients. | Matsumoto Y | Journal of human genetics | 2005 | PMID: 16044199 |
Identification of nine novel DHCR7 missense mutations in patients with Smith-Lemli-Opitz syndrome (SLOS). | Waye JS | Human mutation | 2005 | PMID: 15954111 |
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 |
3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome. | Correa-Cerro LS | Molecular genetics and metabolism | 2005 | PMID: 15670717 |
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 |
Smith-Lemli-Opitz syndrome: carrier frequency and spectrum of DHCR7 mutations in Canada. | Waye JS | Journal of medical genetics | 2002 | PMID: 12070263 |
Novel mutations in the 7-dehydrocholesterol reductase gene of 13 patients with Smith--Lemli--Opitz syndrome. | Jira PE | Annals of human genetics | 2001 | PMID: 11427181 |
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 |
Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping. | Krakowiak PA | American journal of medical genetics | 2000 | PMID: 10995508 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DHCR7 | - | - | - | - |
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Text-mined citations for rs80338856 ...
HelpRecord last updated May 01, 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.