ClinVar Genomic variation as it relates to human health
NM_001360.3(DHCR7):c.3G>A (p.Met1Ile)
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.3G>A (p.Met1Ile)
Variation ID: 6791 Accession: VCV000006791.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q13.4 11: 71444950 (GRCh38) [ NCBI UCSC ] 11: 71155996 (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 24, 2015 Feb 28, 2024 Sep 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001360.3:c.3G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001351.2:p.Met1Ile missense initiator codon variant NM_001163817.2:c.3G>A NP_001157289.1:p.Met1Ile missense initiator codon variant NC_000011.10:g.71444950C>T NC_000011.9:g.71155996C>T NG_012655.2:g.8482G>A LRG_340:g.8482G>A LRG_340t1:c.3G>A LRG_340p1:p.Met1Ile - Protein change
- M1I
- Other names
- M1L
- Canonical SPDI
- NC_000011.10:71444949: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
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 |
935 | 950 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Sep 10, 2023 | RCV000169218.13 | |
Likely pathogenic (4) |
criteria provided, single submitter
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Jul 6, 2023 | RCV001528227.5 |
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
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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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Likely pathogenic
(Sep 28, 2020)
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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: SCV001437372.2
First in ClinVar: Oct 08, 2020 Last updated: Sep 03, 2023 |
Comment:
Variant summary: DHCR7 c.3G>A (p.Met1?; p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the … (more)
Variant summary: DHCR7 c.3G>A (p.Met1?; p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. At-least one report describes evidence supporting alternative translation initiation from the downsteam Methionine codon 59 of the wild-type DHCR7 protein and that the first N-terminal 58 amino acids are not required for enzyme activity apriori (Wassif_1998). Another variant, c.1A>G (p.Met1?, reported as p.Met1Val) has also been reported in a patient with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2005). Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes. c.3G>A has been reported in the literature as a compound heterozygous genotype in at-least three individuals affected with milder clinical manifestations of Smith-Lemli-Opitz Syndrome (example, Waterham_2000, Langius_2003) and has been subsequently cited by others (example, Scalco_2005, Witsch-Baumgartner_2005, Correa-Cerro_2005, Jezela-Stanek_2008). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One clinical diagnostic laboratory has submitted clinical significance assessment as likely pathogenic to ClinVar before 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jul 07, 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: SCV000220478.3
First in ClinVar: Mar 29, 2015 Last updated: Sep 03, 2023 |
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Pathogenic
(Sep 10, 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: SCV001591501.5
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6791). Disruption of the initiator codon … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6791). Disruption of the initiator codon has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 12949967). This variant is present in population databases (rs121909767, gnomAD 0.0009%). This sequence change affects the initiator methionine of the DHCR7 mRNA. The next in-frame methionine is located at codon 59. (less)
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Likely pathogenic
(Jul 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: SCV002818047.2
First in ClinVar: Jan 07, 2023 Last updated: Sep 03, 2023 |
Comment:
As this variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is … (more)
As this variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12949967, 11111101, 23042628, 11767235, 11453964) (less)
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Pathogenic
(Sep 15, 2003)
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no assertion criteria provided
Method: literature only
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SMITH-LEMLI-OPITZ SYNDROME, MILD
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000027389.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 03, 2023 |
Comment on evidence:
Langius et al. (2003) found compound heterozygosity for the common IVS8-1G-C null mutation (602858.0001) and a novel mutation affecting translation initiation of met1 to leu … (more)
Langius et al. (2003) found compound heterozygosity for the common IVS8-1G-C null mutation (602858.0001) and a novel mutation affecting translation initiation of met1 to leu (M1L) in the DHCR7 gene in 2 brothers with a very mild form of Smith-Lemli-Opitz syndrome (SLOS; 270400). The 15-year-old brother was described as having a relatively high forehead and broad nasal bridge as well as a relatively small chin. He showed second and third toe syndactyly and hypospadias. The 10-year-old younger brother likewise had syndactyly of the second and third toes as well as clinodactyly of the left second finger. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928910.2 First in ClinVar: Sep 24, 2021 Last updated: Sep 03, 2023 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001977743.2 First in ClinVar: Oct 16, 2021 Last updated: Sep 03, 2023 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739603.4 First in ClinVar: Jul 07, 2021 Last updated: Sep 03, 2023 |
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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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Mutational spectrum of Smith-Lemli-Opitz syndrome. | Waterham HR | American journal of medical genetics. Part C, Seminars in medical genetics | 2012 | PMID: 23042628 |
Mild Smith-Lemli-Opitz syndrome: further delineation of 5 Polish cases and review of the literature. | Jezela-Stanek A | European journal of medical genetics | 2008 | PMID: 18249054 |
DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. | Scalco FB | American journal of medical genetics. Part A | 2005 | PMID: 15952211 |
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 |
Identification of three patients with a very mild form of Smith-Lemli-Opitz syndrome. | Langius FA | American journal of medical genetics. Part A | 2003 | PMID: 12949967 |
DHCR7 and Smith-Lemli-Opitz syndrome. | Nowaczyk MJ | Clinical and investigative medicine. Medecine clinique et experimentale | 2001 | PMID: 11767235 |
The Smith-Lemli-Opitz syndrome: a novel metabolic way of understanding developmental biology, embryogenesis, and dysmorphology. | Nowaczyk MJ | Clinical genetics | 2001 | PMID: 11453964 |
Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome. | Waterham HR | Biochimica et biophysica acta | 2000 | PMID: 11111101 |
Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. | Wassif CA | American journal of human genetics | 1998 | PMID: 9634533 |
Text-mined citations for rs121909767 ...
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.