This individual has been reported in PMID: 30290151.
ClinVar Genomic variation as it relates to human health
NM_015386.3(COG4):c.1546G>A (p.Gly516Arg)
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_015386.3(COG4):c.1546G>A (p.Gly516Arg)
Variation ID: 449730 Accession: VCV000449730.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 70496367 (GRCh38) [ NCBI UCSC ] 16: 70530270 (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 Dec 19, 2017 May 1, 2024 Nov 23, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_015386.3:c.1546G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056201.2:p.Gly516Arg missense NM_001195139.2:c.1534G>A NP_001182068.2:p.Gly512Arg missense NM_001365426.1:c.1120G>A NP_001352355.1:p.Gly374Arg missense NR_158212.1:n.1505G>A non-coding transcript variant NC_000016.10:g.70496367C>T NC_000016.9:g.70530270C>T NG_027529.1:g.32188G>A - Protein change
- G516R, G374R, G512R
- Other names
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COG4, GLY516ARG, 1546G-A
- Canonical SPDI
- NC_000016.10:70496366: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
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|||
| COG4 | - | - |
GRCh38 GRCh37 |
345 | 398 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 23, 2022 | RCV000522988.9 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Jul 11, 2019 | RCV000710020.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 23, 2017 | RCV000625979.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 17, 2021 | RCV001266583.4 |
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
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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|---|---|---|---|---|---|
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Pathogenic
(Aug 23, 2017)
|
criteria provided, single submitter
Method: research
|
COG4-congenital disorder of glycosylation
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000746583.3 First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018 |
Comment:
This individual has been reported in PMID: 30290151.
Number of individuals with the variant: 1
Clinical Features:
Talipes equinovarus (present) , Speech apraxia (present) , Small for gestational age (present) , Short stature (present) , Short distal phalanx of finger (present) , … (more)
Talipes equinovarus (present) , Speech apraxia (present) , Small for gestational age (present) , Short stature (present) , Short distal phalanx of finger (present) , Severe intrauterine growth retardation (present) , Relative macrocephaly (present) , Prominent scalp veins (present) , Prominent forehead (present) , Premature birth (present) , Poor suck (present) , Lamellar cataract (present) , Intrauterine growth retardation (present) , Induced vaginal delivery (present) , Growth hormone deficiency (present) , Growth delay (present) , Global developmental delay (present) , Enlarged semicircular canal (present) , Dilated vestibule of the inner ear (present) , Dilatated internal auditory canal (present) , Congenital bilateral ptosis (present) , Cervical spinal canal stenosis (present) , Blue sclerae (present) , Birth length less than 3rd percentile (present) , Bilateral talipes equinovarus (present) , Bilateral sensorineural hearing impairment (present) , Apraxia (present) , Aplasia/Hypoplasia of the middle phalanges of the hand (present) , Abnormality of cochlea (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: White
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2015-12-11
Testing laboratory interpretation: not provided
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Pathogenic
(Jul 11, 2019)
|
criteria provided, single submitter
Method: curation
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Microcephalic osteodysplastic dysplasia, Saul-Wilson type
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000996399.1
First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019 |
Comment:
This variant is interpreted as a Pathogenic for Saul-Wilson syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2; PS4-Moderate; PM6-Strong; PP3; PS3
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Pathogenic
(Nov 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000618093.4
First in ClinVar: Dec 19, 2017 Last updated: Dec 03, 2022 |
Comment:
Published functional studies demonstrate a significant increase in core proteins of HSPGs accumulation on the cell surface of G516R mutant cell lines and increased secretion … (more)
Published functional studies demonstrate a significant increase in core proteins of HSPGs accumulation on the cell surface of G516R mutant cell lines and increased secretion of the SIL1 protein; findings which support a gain of function effect of the G516R variant (Sumya et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34603392, 31949312, 30290151, 33688625, 34595172, 35455576, 36393834) (less)
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Pathogenic
(Oct 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002817259.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant appears to occur de novo in an individual tested at Athena Diagnostics and in multiple individuals with clinical features consistent with autosomal dominant … (more)
This variant appears to occur de novo in an individual tested at Athena Diagnostics and in multiple individuals with clinical features consistent with autosomal dominant Saul-Wilson syndrome (PMID 30290151). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
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Pathogenic
(Mar 31, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017407.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444759.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.1546G>A (p.G516R) alteration is located in exon 12 (coding exon 12) of the COG4 gene. This alteration results from a G to A substitution … (more)
The c.1546G>A (p.G516R) alteration is located in exon 12 (coding exon 12) of the COG4 gene. This alteration results from a G to A substitution at nucleotide position 1546, causing the glycine (G) at amino acid position 516 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The p.G516R alteration has been reported as a recurrent de novo alteration in several patients with Saul-Wilson syndrome (Ferreira, 2018). This amino acid position is highly conserved in available vertebrate species. Fibroblasts from patients with the p.G516R alteration have been shown to have abnormal Golgi morphology and decreased Golgi volume compared to control samples. Glycan analysis and glycosylation status were not measurably different between patients and controls; however there was evidence of altered Golgi-dependent glycosylation and abnormal Golgi trafficking in patients (Ferreira, 2018) . The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Nov 29, 2018)
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no assertion criteria provided
Method: literature only
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SAUL-WILSON SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000840385.2
First in ClinVar: Oct 19, 2018 Last updated: Dec 02, 2018 |
Comment on evidence:
In 11 patients with Saul-Wilson syndrome (SWILS; 618150), including patient 1 in the report of Hersh et al. (1994), Ferreira et al. (2018) identified a … (more)
In 11 patients with Saul-Wilson syndrome (SWILS; 618150), including patient 1 in the report of Hersh et al. (1994), Ferreira et al. (2018) identified a de novo heterozygous c.1546G-A transition (c.1546G-A, NM_015386.2) in the COG4 gene, resulting in a gly516-to-arg (G516R) substitution. The mutations, which were found by whole-exome or whole-genome sequencing, were confirmed by Sanger sequencing. Compared to control cell lines, fibroblasts from affected individuals showed normal mRNA expression and protein level of COG4 and other COG subunits, confirming that the variant leads to production of a stable protein. Protein modeling predicted the loss of a loop structure in the mutant protein; however, binding of COG4 to other COG subunits was not altered. (less)
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not provided
(-)
|
no classification provided
Method: literature only
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Microcephalic osteodysplastic dysplasia, Saul-Wilson type
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV001245260.2
First in ClinVar: May 04, 2020 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
This variant is interpreted as a Pathogenic for Saul-Wilson syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2; PS4-Moderate; PM6-Strong; PP3; PS3
Comment:
Published functional studies demonstrate a significant increase in core proteins of HSPGs accumulation on the cell surface of G516R mutant cell lines and increased secretion of the SIL1 protein; findings which support a gain of function effect of the G516R variant (Sumya et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34603392, 31949312, 30290151, 33688625, 34595172, 35455576, 36393834)
Comment:
This variant appears to occur de novo in an individual tested at Athena Diagnostics and in multiple individuals with clinical features consistent with autosomal dominant Saul-Wilson syndrome (PMID 30290151). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
The c.1546G>A (p.G516R) alteration is located in exon 12 (coding exon 12) of the COG4 gene. This alteration results from a G to A substitution at nucleotide position 1546, causing the glycine (G) at amino acid position 516 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The p.G516R alteration has been reported as a recurrent de novo alteration in several patients with Saul-Wilson syndrome (Ferreira, 2018). This amino acid position is highly conserved in available vertebrate species. Fibroblasts from patients with the p.G516R alteration have been shown to have abnormal Golgi morphology and decreased Golgi volume compared to control samples. Glycan analysis and glycosylation status were not measurably different between patients and controls; however there was evidence of altered Golgi-dependent glycosylation and abnormal Golgi trafficking in patients (Ferreira, 2018) . The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is 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 individual has been reported in PMID: 30290151.
Comment:
This variant is interpreted as a Pathogenic for Saul-Wilson syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PM2; PS4-Moderate; PM6-Strong; PP3; PS3
Comment:
Published functional studies demonstrate a significant increase in core proteins of HSPGs accumulation on the cell surface of G516R mutant cell lines and increased secretion of the SIL1 protein; findings which support a gain of function effect of the G516R variant (Sumya et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34603392, 31949312, 30290151, 33688625, 34595172, 35455576, 36393834)
Comment:
This variant appears to occur de novo in an individual tested at Athena Diagnostics and in multiple individuals with clinical features consistent with autosomal dominant Saul-Wilson syndrome (PMID 30290151). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
The c.1546G>A (p.G516R) alteration is located in exon 12 (coding exon 12) of the COG4 gene. This alteration results from a G to A substitution at nucleotide position 1546, causing the glycine (G) at amino acid position 516 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The p.G516R alteration has been reported as a recurrent de novo alteration in several patients with Saul-Wilson syndrome (Ferreira, 2018). This amino acid position is highly conserved in available vertebrate species. Fibroblasts from patients with the p.G516R alteration have been shown to have abnormal Golgi morphology and decreased Golgi volume compared to control samples. Glycan analysis and glycosylation status were not measurably different between patients and controls; however there was evidence of altered Golgi-dependent glycosylation and abnormal Golgi trafficking in patients (Ferreira, 2018) . The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Defining the clinical phenotype of Saul-Wilson syndrome. | Ferreira CR | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31949312 |
| A Recurrent De Novo Heterozygous COG4 Substitution Leads to Saul-Wilson Syndrome, Disrupted Vesicular Trafficking, and Altered Proteoglycan Glycosylation. | Ferreira CR | American journal of human genetics | 2018 | PMID: 30290151 |
| Microcephalic osteodysplastic dysplasia. | Hersh JH | American journal of medical genetics | 1994 | PMID: 8074143 |
Text-mined citations for rs1555575860 ...
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 May 08, 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.