ClinVar Genomic variation as it relates to human health
NM_001360.3(DHCR7):c.976G>T (p.Val326Leu)
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.976G>T (p.Val326Leu)
Variation ID: 6785 Accession: VCV000006785.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.4 11: 71435827 (GRCh38) [ NCBI UCSC ] 11: 71146873 (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 Jun 17, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001360.3:c.976G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001351.2:p.Val326Leu missense NM_001163817.2:c.976G>T NP_001157289.1:p.Val326Leu missense NC_000011.10:g.71435827C>A NC_000011.9:g.71146873C>A NG_012655.2:g.17605G>T LRG_340:g.17605G>T LRG_340t1:c.976G>T LRG_340p1:p.Val326Leu Q9UBM7:p.Val326Leu - Protein change
- V326L
- Other names
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- Canonical SPDI
- NC_000011.10:71435826:C: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 0.00002
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
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
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 |
932 | 947 |
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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Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000007187.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 6, 2023 | RCV001550331.5 |
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. |
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Pathogenic
(May 22, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697860.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
Variant summary: The DHCR7 c.976G>T (p.Val326Leu) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low … (more)
Variant summary: The DHCR7 c.976G>T (p.Val326Leu) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. This variant was found in 5/104104 control chromosomes at a frequency of 0.000048, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals. Authors have also indicated the variant to be a common mutation (Ciara_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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: SCV000893241.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Apr 06, 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: SCV001770642.4
First in ClinVar: Aug 07, 2021 Last updated: Apr 15, 2023 |
Comment:
Published functional studies demonstrate a damaging effect as the DHCR7 protein expression was significantly reduced in cells expressing the V326L variant compared to wildype, suggesting … (more)
Published functional studies demonstrate a damaging effect as the DHCR7 protein expression was significantly reduced in cells expressing the V326L variant compared to wildype, suggesting the variant impairs protein stability due to misfolding or defective transports (Fitzky et al., 1998); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 9653161, 22975760, 26887953, 11175299, 32257592, 34426522, 31589614, 34308104, 31840946, 33836803, 33890232) (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Smith-Lemli-Opitz syndrome
Affected status: no
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051751.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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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: SCV001163693.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Pathogenic
(Dec 20, 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: SCV001193943.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_001360.2(DHCR7):c.976G>T(V326L) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and is associated with moderate or mild forms of the disease. Sources cited for … (more)
NM_001360.2(DHCR7):c.976G>T(V326L) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and is associated with moderate or mild forms of the disease. Sources cited for classification include the following: PMID 15521979. Classification of NM_001360.2(DHCR7):c.976G>T(V326L) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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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Likely pathogenic
(Aug 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Smith-Lemli-Opitz syndrome
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061512.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 12, 2022 |
Comment:
PS3, PM2, PM3
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Pathogenic
(Jan 28, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000835626.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 326 of the DHCR7 protein (p.Val326Leu). … (more)
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 326 of the DHCR7 protein (p.Val326Leu). This variant is present in population databases (rs80338859, gnomAD 0.005%). This missense change has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 9653161, 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: 6785). 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 80%. Studies have shown that this missense change alters DHCR7 gene expression (PMID: 9653161). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 2004)
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no assertion criteria provided
Method: literature only
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SMITH-LEMLI-OPITZ SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027383.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 24, 2015 |
Comment on evidence:
In 5 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Fitzky et al. (1998) found a G-to-T transversion at nucleotide 976 of the DHCR7 gene, resulting in … (more)
In 5 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Fitzky et al. (1998) found a G-to-T transversion at nucleotide 976 of the DHCR7 gene, resulting in a val326-to-leu (V326L) amino acid substitution. In 3 of these patients the V326L mutation was found in compound heterozygous state, whereas in the other 2 patients the V326L mutation was found on 1 allele only. SSCP analysis failed to reveal a second mutation in these 2 patients. In a screen of 32 patients with SLOS, Yu et al. (2000) found that the V326L mutation accounted for 5 of 64 alleles (7.8%), making it the third most common mutation observed in their cohort. The first and second most prevalent mutations were IVS8-1G-C (602858.0001) and T93M (602858.0009), respectively. Witsch-Baumgartner et al. (2001) detected the V326L mutation on 16 of 118 alleles (13.6%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected (Poland, 23.3% of alleles; Germany/Austria, 18.2%; Great Britain, 2.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that 5 V326L chromosomes shared the same haplotype and therefore provided evidence for a founder effect. Ciara et al. (2004) found the V326L mutation in 19 of 68 alleles (28%) in a study of 37 ethnic Polish patients. (less)
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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: SCV002093017.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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: SCV000040856.2
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 |
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 |
Recent insights into the Smith-Lemli-Opitz syndrome. | Yu H | Clinical genetics | 2005 | PMID: 16207203 |
DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome. | Ciara E | Clinical genetics | 2004 | PMID: 15521979 |
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 |
Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. | Yu H | Human molecular genetics | 2000 | PMID: 10814720 |
Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. | Fitzky BU | Proceedings of the National Academy of Sciences of the United States of America | 1998 | PMID: 9653161 |
Text-mined citations for rs80338859 ...
HelpRecord last updated Sep 29, 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.