ClinVar Genomic variation as it relates to human health
NM_000193.4(SHH):c.1147G>A (p.Ala383Thr)
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_000193.4(SHH):c.1147G>A (p.Ala383Thr)
Variation ID: 8886 Accession: VCV000008886.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.3 7: 155803142 (GRCh38) [ NCBI UCSC ] 7: 155595836 (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 Oct 1, 2013 Feb 14, 2024 Sep 14, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000193.4:c.1147G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000184.1:p.Ala383Thr missense NM_001310462.2:c.302-2897G>A intron variant NC_000007.14:g.155803142C>T NC_000007.13:g.155595836C>T NG_007504.2:g.14132G>A Q15465:p.Ala383Thr - Protein change
- A383T
- Other names
- A384T
- c.1147G>A
- Canonical SPDI
- NC_000007.14:155803141: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.
Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 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
Help
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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SHH | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
329 | 565 |
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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Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Sep 14, 2022 | RCV000009436.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2020 | RCV000662212.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 5, 2018 | RCV000662213.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 5, 2018 | RCV000662214.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 18, 2019 | RCV003137506.4 |
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
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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Uncertain significance
(Jan 29, 2020)
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criteria provided, single submitter
Method: clinical testing
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Schizencephaly
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367474.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in … (more)
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. (less)
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Uncertain significance
(Sep 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Holoprosencephaly 3
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003524407.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 8886). This variant is also known as Ala384Thr. This missense change has been observed in individual(s) … (more)
ClinVar contains an entry for this variant (Variation ID: 8886). This variant is also known as Ala384Thr. This missense change has been observed in individual(s) with holoprosencephaly (PMID: 9302262). This variant is present in population databases (rs137853341, gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 383 of the SHH protein (p.Ala383Thr). 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 not expected to disrupt SHH protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SHH function (PMID: 15292211, 32939873). (less)
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Uncertain significance
(Mar 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Single Central Incisor Syndrome
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784571.2
First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 30-39 years
Sex: female
Geographic origin: Iran
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Uncertain significance
(Mar 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Holoprosencephaly 3
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784568.2
First in ClinVar: Oct 01, 2013 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 30-39 years
Sex: female
Geographic origin: Iran
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Uncertain significance
(Mar 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Schizencephaly
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784569.2
First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 30-39 years
Sex: female
Geographic origin: Iran
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Uncertain significance
(Mar 05, 2018)
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criteria provided, single submitter
Method: clinical testing
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Microphthalmia, isolated, with coloboma 5
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000784570.2
First in ClinVar: Jul 13, 2018 Last updated: Dec 11, 2022 |
Number of individuals with the variant: 1
Age: 30-39 years
Sex: female
Geographic origin: Iran
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Uncertain significance
(Dec 18, 2019)
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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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Revvity Omics, Revvity
Accession: SCV003820001.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 01, 1997)
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no assertion criteria provided
Method: literature only
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HOLOPROSENCEPHALY 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029654.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 24, 2018 |
Comment on evidence:
In a child with holoprosencephaly (HPE3; 142945), Roessler et al. (1997) identified a G-to-A transition in the SHH gene that resulted in an ala-to-thr substitution … (more)
In a child with holoprosencephaly (HPE3; 142945), Roessler et al. (1997) identified a G-to-A transition in the SHH gene that resulted in an ala-to-thr substitution at codon 384 (A384T). In a screen of 184 sporadic HPE cases, this was the only sequence variation found that predicted a change in the primary coding sequence of the SHH protein. The parents of this child were unavailable for analysis. (less)
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pathologic
(Aug 29, 2013)
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no assertion criteria provided
Method: curation
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Holoprosencephaly
Affected status: not provided
Allele origin:
not provided
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GeneReviews
Accession: SCV000087133.1
First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2013 |
Comment:
Converted during submission to Pathogenic.
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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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Functional analysis of Sonic Hedgehog variants associated with holoprosencephaly in humans using a CRISPR/Cas9 zebrafish model. | Hong S | Human mutation | 2020 | PMID: 32939873 |
Holoprosencephaly Overview. | Adam MP | - | 2020 | PMID: 20301702 |
Functional characterization of sonic hedgehog mutations associated with holoprosencephaly. | Traiffort E | The Journal of biological chemistry | 2004 | PMID: 15292211 |
Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. | Roessler E | Human molecular genetics | 1997 | PMID: 9302262 |
Cytogenetic rearrangements involving the loss of the Sonic Hedgehog gene at 7q36 cause holoprosencephaly. | Roessler E | Human genetics | 1997 | PMID: 9254845 |
Text-mined citations for rs137853341 ...
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.