ClinVar Genomic variation as it relates to human health
NM_001360.3(DHCR7):c.1139G>A (p.Cys380Tyr)
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.1139G>A (p.Cys380Tyr)
Variation ID: 189069 Accession: VCV000189069.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.4 11: 71435664 (GRCh38) [ NCBI UCSC ] 11: 71146710 (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 Mar 29, 2015 Oct 8, 2024 Nov 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001360.3:c.1139G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001351.2:p.Cys380Tyr missense NM_001163817.2:c.1139G>A NP_001157289.1:p.Cys380Tyr missense NC_000011.10:g.71435664C>T NC_000011.9:g.71146710C>T NG_012655.2:g.17768G>A LRG_340:g.17768G>A LRG_340t1:c.1139G>A LRG_340p1:p.Cys380Tyr Q9UBM7:p.Cys380Tyr - Protein change
- C380Y
- Other names
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- Canonical SPDI
- NC_000011.10:71435663: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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
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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 |
932 | 947 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Nov 7, 2023 | RCV000169472.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2020 | RCV001171660.21 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 3, 2016 | RCV002453569.3 |
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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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: SCV001163687.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Likely pathogenic
(Nov 25, 2014)
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criteria provided, single submitter
Method: literature only
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Smith-Lemli-Opitz syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220916.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Apr 08, 2022)
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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: SCV002779328.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 07, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001225668.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 380 of the DHCR7 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 380 of the DHCR7 protein (p.Cys380Tyr). This variant is present in population databases (rs779709646, gnomAD 0.0009%). This missense change has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 10677299, 15896653, 25405082). ClinVar contains an entry for this variant (Variation ID: 189069). 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.Cys380 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15896653, 17441222). 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
(Feb 03, 2016)
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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: SCV002612936.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.C380Y pathogenic mutation (also known as c.1139G>A), located in coding exon 7 of the DHCR7 gene, results from a G to A substitution at … (more)
The p.C380Y pathogenic mutation (also known as c.1139G>A), located in coding exon 7 of the DHCR7 gene, results from a G to A substitution at nucleotide position 1139. The cysteine at codon 380 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been observed in homozygous and heterozygous states in multiple individuals with clinical and biochemical features characteristic of Smith-Lemli-Optiz syndrome (SLOS) (Witsch-Baumgartner M, et al. Am. J. Hum. Genet. 2000; 66(2):402-12, Pappu AS, et al. J. Lipid Res. 2006; 47(12):2789-98, Bukelis I, et al. Am J Psychiatry 2007; 164(11):1655-61). In one study using an immunoreactivity assay, protein expression of this alteration was observed to be 40% of wild type levels (Witsch-Baumgartner M, et al. Am. J. Hum. Genet. 2000; 66(2):402-12). In addition, a different mutation located at the same position, p.C380R, has been detected in individuals with SLOS, and was shown to decrease protein expression to 5% of wild type levels (Witsch-Baumgartner M, et al. Am. J. Hum. Genet. 2000; 66(2):402-12, Nowaczyk MJ, et al. Am. J. Med. Genet. 2001; 103(3):223-5). Based on the supporting evidence, p.C380Y is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Feb 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334463.24
First in ClinVar: Jun 08, 2020 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 3
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Likely pathogenic
(Oct 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Smith-Lemli-Opitz syndrome
Affected status: yes
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Study: Clinvar_gadteam_Clinical_exome_analysis_3
Accession: SCV000803782.1 First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015 |
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Pathogenic
(Mar 17, 2017)
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no assertion criteria provided
Method: clinical testing
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Smith-Lemli-Opitz syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002093008.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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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Elevated Autophagy and Mitochondrial Dysfunction in the Smith-Lemli-Opitz Syndrome. | Chang S | Molecular genetics and metabolism reports | 2014 | PMID: 25405082 |
Molecular screening of Smith-Lemli-Opitz syndrome in pregnant women from the Czech Republic. | Blahakova I | Journal of inherited metabolic disease | 2007 | PMID: 17994283 |
Smith-Lemli-Opitz syndrome and autism spectrum disorder. | Bukelis I | The American journal of psychiatry | 2007 | PMID: 17974928 |
Effects of cholesterol and simvastatin treatment in patients with Smith-Lemli-Opitz syndrome (SLOS). | Haas D | Journal of inherited metabolic disease | 2007 | PMID: 17497248 |
Prenatal diagnosis of Smith-Lemli-Opitz syndrome (SLOS) by DHCR7 mutation analysis. | Waye JS | Prenatal diagnosis | 2007 | PMID: 17441222 |
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 |
Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith-Lemli-Opitz syndrome fibroblasts. | Wassif CA | Molecular genetics and metabolism | 2005 | PMID: 15896653 |
Smith-Lemli-Opitz syndrome: carrier frequency and spectrum of DHCR7 mutations in Canada. | Waye JS | Journal of medical genetics | 2002 | PMID: 12070263 |
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 |
Text-mined citations for rs779709646 ...
HelpRecord last updated Oct 08, 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.