This variant is interpreted as a Likely Pathogenic, for Shprintzen-Goldberg craniosynostosis syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24736733). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:23023332,23103230,24736733).
ClinVar Genomic variation as it relates to human health
NM_003036.4(SKI):c.100G>A (p.Gly34Ser)
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003036.4(SKI):c.100G>A (p.Gly34Ser)
Variation ID: 37261 Accession: VCV000037261.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p36.33 1: 2228866 (GRCh38) [ NCBI UCSC ] 1: 2160305 (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 Oct 11, 2015 Jan 7, 2023 Apr 26, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003036.4:c.100G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003027.1:p.Gly34Ser missense NC_000001.11:g.2228866G>A NC_000001.10:g.2160305G>A NG_013084.1:g.5172G>A P12755:p.Gly34Ser - Protein change
- G34S
- Other names
-
p.G34S:GGC>AGC
NM_003036.3(SKI):c.100G>A(p.Gly34Ser)
- Canonical SPDI
- NC_000001.11:2228865: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.
- -
- Links
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. |
|||
| SKI | No evidence available | No evidence available |
GRCh38 GRCh37 |
1110 | 1257 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Apr 26, 2022 | RCV000030819.34 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 11, 2014 | RCV000200686.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 15, 2016 | RCV000624509.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Shprintzen-Goldberg syndrome
Affected status: yes
Allele origin:
de novo
|
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine
Accession: SCV000266520.1
First in ClinVar: Apr 03, 2016 Last updated: Apr 03, 2016 |
Family history: no
|
|
|
Pathogenic
(Sep 15, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741801.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Hearing impairment (present) , Global developmental delay (present) , Ventriculomegaly (present) , Clubfoot (present) , High, narrow palate (present) , Long fingers (present) , Short … (more)
Hearing impairment (present) , Global developmental delay (present) , Ventriculomegaly (present) , Clubfoot (present) , High, narrow palate (present) , Long fingers (present) , Short philtrum (present) , Thin upper lip vermilion (present) , Micrognathia (present) , Hypertelorism (present) , Depressed nasal bridge (present) , Horizontal nystagmus (present) , Episodic vomiting (present) , Lethargy (present) , Failure to thrive (present) , Muscular hypotonia (present) (less)
Sex: female
Ethnicity/Population group: Caucasian
|
|
|
Likely pathogenic
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Shprintzen-Goldberg syndrome
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803523.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
Comment:
This variant is interpreted as a Likely Pathogenic, for Shprintzen-Goldberg craniosynostosis syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM5 => Novel … (more)
This variant is interpreted as a Likely Pathogenic, for Shprintzen-Goldberg craniosynostosis syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24736733). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:23023332,23103230,24736733). (less)
|
|
|
Pathogenic
(Dec 11, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000250672.11
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
p.Gly34Ser (GGC>AGC): c.100 G>A in exon 1 of the SKI gene (NM_003036.3) The G34S mutation in the SKI gene has been reported in three individuals … (more)
p.Gly34Ser (GGC>AGC): c.100 G>A in exon 1 of the SKI gene (NM_003036.3) The G34S mutation in the SKI gene has been reported in three individuals with clinical diagnoses of SGS (Doyle et al., 2012; Carmignac et al., 2012, Schepers et al., 2014). The Gly34 residue appears to be a recurrent mutation hotspot in the R-SMAD binding domain of the SKI gene, as different mutations impacting this amino acid (G34D, G34C, G34V) have been reported (Doyle et al., 2012; Carmignac et al., 2012, Schepers et al., 2014). Mutations in nearby residues (S31L, L32V, L32P, P35S, P35Q) have also been reported in association with SGS, further supporting the functional importance of this region of the protein. G34S results in a non-conservative amino acid substitution of Glycine at a position that is conserved, when present, across species. This variant was found in TAADV2-1,SKI (less)
|
|
|
Pathogenic
(Apr 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Shprintzen-Goldberg syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511658.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: SKI c.100G>A (p.Gly34Ser) results in a non-conservative amino acid change located in the R-SMAD domain (Carmignac_2012) of the encoded protein sequence. Five of … (more)
Variant summary: SKI c.100G>A (p.Gly34Ser) results in a non-conservative amino acid change located in the R-SMAD domain (Carmignac_2012) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 95400 control chromosomes. c.100G>A has been reported in the literature in individuals affected with Shprintzen-Goldberg Syndrome (example, Doyle_2012, Carmignac_2012, Au_2014, Schepers_2015, Nayak_2021). Mutations in exon 1 of SKI have recently been identified as being responsible for approximately 90% of reported individuals diagnosed clinically with Shprintzen-Goldberg syndrome (Au_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2015)
|
no assertion criteria provided
Method: literature only
|
SHPRINTZEN-GOLDBERG CRANIOSYNOSTOSIS SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000053494.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 19, 2018 |
Comment on evidence:
In a 21-year-old man with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Doyle et al. (2012) identified heterozygosity for a 100G-A transition in exon 1 of the … (more)
In a 21-year-old man with Shprintzen-Goldberg craniosynostosis syndrome (SGS; 182212), Doyle et al. (2012) identified heterozygosity for a 100G-A transition in exon 1 of the SKI gene, resulting in a gly34-to-ser (G34S) substitution at a highly conserved residue in the SMAD2 (601366)/3 (603109)-binding domain. The mutation was not found in dbSNP (build 134), the 1000 Genomes Project database, or more than 10,000 exomes reported on the National Heart, Lung, and Blood Institute Exome Variant Server. In an 11-year-old girl with SGS, whose features included aortic root dilation and mitral valve prolapse, Carmignac et al. (2012) identified heterozygosity for the G34S mutation in the SKI gene. In a 10-year-old boy with SGS, Schepers et al. (2015) identified heterozygosity for a de novo G34S substitution in the SKI gene. He did not exhibit mitral valve prolapse, aortic root dilation, arterial tortuosity, or aneurysms. (less)
|
|
|
Pathogenic
(Jan 01, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Shprintzen-Goldberg syndrome
Affected status: yes
Allele origin:
de novo
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV001427382.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
|
Comment:
Comment:
p.Gly34Ser (GGC>AGC): c.100 G>A in exon 1 of the SKI gene (NM_003036.3) The G34S mutation in the SKI gene has been reported in three individuals with clinical diagnoses of SGS (Doyle et al., 2012; Carmignac et al., 2012, Schepers et al., 2014). The Gly34 residue appears to be a recurrent mutation hotspot in the R-SMAD binding domain of the SKI gene, as different mutations impacting this amino acid (G34D, G34C, G34V) have been reported (Doyle et al., 2012; Carmignac et al., 2012, Schepers et al., 2014). Mutations in nearby residues (S31L, L32V, L32P, P35S, P35Q) have also been reported in association with SGS, further supporting the functional importance of this region of the protein. G34S results in a non-conservative amino acid substitution of Glycine at a position that is conserved, when present, across species. This variant was found in TAADV2-1,SKI
Comment:
Variant summary: SKI c.100G>A (p.Gly34Ser) results in a non-conservative amino acid change located in the R-SMAD domain (Carmignac_2012) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 95400 control chromosomes. c.100G>A has been reported in the literature in individuals affected with Shprintzen-Goldberg Syndrome (example, Doyle_2012, Carmignac_2012, Au_2014, Schepers_2015, Nayak_2021). Mutations in exon 1 of SKI have recently been identified as being responsible for approximately 90% of reported individuals diagnosed clinically with Shprintzen-Goldberg syndrome (Au_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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. |
Comment:
This variant is interpreted as a Likely Pathogenic, for Shprintzen-Goldberg craniosynostosis syndrome, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24736733). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:23023332,23103230,24736733).
Comment:
p.Gly34Ser (GGC>AGC): c.100 G>A in exon 1 of the SKI gene (NM_003036.3) The G34S mutation in the SKI gene has been reported in three individuals with clinical diagnoses of SGS (Doyle et al., 2012; Carmignac et al., 2012, Schepers et al., 2014). The Gly34 residue appears to be a recurrent mutation hotspot in the R-SMAD binding domain of the SKI gene, as different mutations impacting this amino acid (G34D, G34C, G34V) have been reported (Doyle et al., 2012; Carmignac et al., 2012, Schepers et al., 2014). Mutations in nearby residues (S31L, L32V, L32P, P35S, P35Q) have also been reported in association with SGS, further supporting the functional importance of this region of the protein. G34S results in a non-conservative amino acid substitution of Glycine at a position that is conserved, when present, across species. This variant was found in TAADV2-1,SKI
Comment:
Variant summary: SKI c.100G>A (p.Gly34Ser) results in a non-conservative amino acid change located in the R-SMAD domain (Carmignac_2012) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 95400 control chromosomes. c.100G>A has been reported in the literature in individuals affected with Shprintzen-Goldberg Syndrome (example, Doyle_2012, Carmignac_2012, Au_2014, Schepers_2015, Nayak_2021). Mutations in exon 1 of SKI have recently been identified as being responsible for approximately 90% of reported individuals diagnosed clinically with Shprintzen-Goldberg syndrome (Au_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinically relevant variants in a large cohort of Indian patients with Marfan syndrome and related disorders identified by next-generation sequencing. | Nayak SS | Scientific reports | 2021 | PMID: 33436942 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome. | Schepers D | European journal of human genetics : EJHG | 2015 | PMID: 24736733 |
| De novo exon 1 missense mutations of SKI and Shprintzen-Goldberg syndrome: two new cases and a clinical review. | Au PY | American journal of medical genetics. Part A | 2014 | PMID: 24357594 |
| In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome. | Carmignac V | American journal of human genetics | 2012 | PMID: 23103230 |
| Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. | Doyle AJ | Nature genetics | 2012 | PMID: 23023332 |
| Ski and SnoN, potent negative regulators of TGF-beta signaling. | Deheuninck J | Cell research | 2009 | PMID: 19114989 |
Text-mined citations for rs387907306 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Jun 23, 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.