ClinVar Genomic variation as it relates to human health
NM_015330.6(SPECC1L):c.3247G>A (p.Gly1083Ser)
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.
Likely pathogenic(3); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_015330.6(SPECC1L):c.3247G>A (p.Gly1083Ser)
Variation ID: 183672 Accession: VCV000183672.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q11.23 22: 24412690 (GRCh38) [ NCBI UCSC ] 22: 24808658 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 10, 2017 Apr 6, 2024 Mar 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_015330.6:c.3247G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056145.5:p.Gly1083Ser missense NM_001145468.4:c.3247G>A NP_001138940.4:p.Gly1083Ser missense NM_001254732.3:c.3130G>A NP_001241661.3:p.Gly1044Ser missense NM_001254733.2:c.445G>A NP_001241662.2:p.Gly149Ser missense NM_015330.4:c.3247G>A NM_015330.5:c.3247G>A NR_103546.1:n.3677G>A non-coding transcript variant NC_000022.11:g.24412690G>A NC_000022.10:g.24808658G>A NG_031915.2:g.146869G>A - Protein change
- G1083S, G149S, G1044S
- Other names
- -
- Canonical SPDI
- NC_000022.11:24412689:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
SPECC1L | - | - |
GRCh38 GRCh37 |
- | 364 | |
SPECC1L-ADORA2A | - | - | - | GRCh38 | - | 326 |
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
Help
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Mar 25, 2024 | RCV002221207.13 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Dec 20, 2022 | RCV003137691.12 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Dec 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003935469.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: proteins with the G1083S variant are defective in stabilizing microtubules (Kruszka et al., 2015); In silico analysis supports … (more)
Published functional studies demonstrate a damaging effect: proteins with the G1083S variant are defective in stabilizing microtubules (Kruszka et al., 2015); 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: 25412741, 30472488, 31953237, 3228142) (less)
|
|
Likely pathogenic
(Jul 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Teebi hypertelorism syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002549846.2
First in ClinVar: Jul 23, 2022 Last updated: Aug 23, 2023 |
Comment:
Criteria applied: PP1_STR,PS3_SUP,PS4_SUP,PM1_SUP,PP3
Clinical Features:
Moderate global developmental delay (present) , Neonatal hypoglycemia (present) , Corpus callosum, agenesis of (present) , Obesity (present)
Sex: male
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Teebi hypertelorism syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Lifecell International Pvt. Ltd
Accession: SCV003924055.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
A Heterozygous Missense variant c.3247G>A in Exon 16 of the SPECC1L gene that results in the amino acid substitution p.Gly1083Ser was identified. The observed variant … (more)
A Heterozygous Missense variant c.3247G>A in Exon 16 of the SPECC1L gene that results in the amino acid substitution p.Gly1083Ser was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes and novel in genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic (Variant ID: 183672). This variant has previously been reported in the patient affected with BBB syndrome (Kruszka P et al 2015) Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
|
|
Uncertain significance
(Feb 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003824537.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Uncertain significance
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Teebi hypertelorism syndrome 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004806431.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
Pathogenic
(Feb 01, 2015)
|
no assertion criteria provided
Method: literature only
|
TEEBI HYPERTELORISM SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000212271.3
First in ClinVar: Mar 24, 2015 Last updated: Apr 12, 2022 |
Comment on evidence:
In affected members of a family with Teebi hypertelorism syndrome-1 (TBHS1; 145420), originally reported by Allanson (1988), Kruszka et al. (2015) identified a heterozygous c.3247G-A … (more)
In affected members of a family with Teebi hypertelorism syndrome-1 (TBHS1; 145420), originally reported by Allanson (1988), Kruszka et al. (2015) identified a heterozygous c.3247G-A transition in the SPECC1L gene, resulting in a gly1083-to-ser (G1083S) substitution in the C-terminal calponin homology domain. The mutation was not present in the 1000 Genomes Project or Exome Sequencing Project databases or in over 1,500 in-house control exomes. The proband was 1 of 19 patients with a similar disorder who underwent direct sequencing of the SPECC1L gene. In vitro functional expression studies showed that the mutant protein had an abnormal punctate expression pattern and a drastically reduced ability to stabilize microtubules. Although the phenotype in this family was originally thought to represent an unusual form of autosomal dominant Opitz GBBB syndrome, Bhoj et al. (2019) concluded that the pattern of developmental anomalies caused by mutation in SPECC1L was distinct enough from that of classic Opitz GBBB syndrome (see 300000) that the phenotype should be referred to as Teebi syndrome. (less)
|
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 |
---|---|---|---|---|
Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes. | Bhoj EJ | European journal of medical genetics | 2019 | PMID: 30472488 |
Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome. | Kruszka P | Journal of medical genetics | 2015 | PMID: 25412741 |
G syndrome: an unusual family. | Allanson JE | American journal of medical genetics | 1988 | PMID: 3228142 |
Text-mined citations for rs786201031 ...
HelpRecord last updated Jun 02, 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.