ClinVar Genomic variation as it relates to human health
NM_000089.4(COL1A2):c.1072G>A (p.Gly358Ser)
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
-
NM_000089.4(COL1A2):c.1072G>A (p.Gly358Ser)
Variation ID: 456802 Accession: VCV000456802.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q21.3 7: 94410278 (GRCh38) [ NCBI UCSC ] 7: 94039590 (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 Dec 26, 2017 Apr 15, 2024 Nov 29, 2022 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000089.4:c.1072G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000080.2:p.Gly358Ser missense NC_000007.14:g.94410278G>A NC_000007.13:g.94039590G>A NG_007405.1:g.20718G>A LRG_2:g.20718G>A LRG_2t1:c.1072G>A LRG_2p1:p.Gly358Ser - Protein change
- G358S
- Other names
- -
- Canonical SPDI
- NC_000007.14:94410277: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.
-
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. |
|||
COL1A2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
2054 | 2075 |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 24, 2019 | RCV001091391.24 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2022 | RCV001809476.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 29, 2022 | RCV002231005.11 | |
Pathogenic (2) |
criteria provided, single submitter
|
Jul 29, 2021 | RCV001542470.11 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 13, 2021 | RCV002490955.8 |
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
(Sep 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001771057.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; … (more)
Not observed in large population cohorts (Lek et al., 2016); Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 31299979, 16705691, 29150909, 21520333, 25525159, 26432670, 22589248, 26371943) (less)
|
|
Pathogenic
(Jul 29, 2021)
|
criteria provided, single submitter
Method: research
|
Osteogenesis imperfecta, perinatal lethal
Affected status: yes
Allele origin:
unknown
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-SouthSeq
Accession: SCV001787150.1 First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021 |
Comment:
ACMG codes: PS4M; PM1; PM2; PP3; PP5
Number of individuals with the variant: 1
Clinical Features:
Fetal growth restriction (present) , Birth length less than 3rd percentile (present) , Hearing impairment (present) , Abnormality of the face (present) , Atrial septal … (more)
Fetal growth restriction (present) , Birth length less than 3rd percentile (present) , Hearing impairment (present) , Abnormality of the face (present) , Atrial septal defect (present) , Hypotonia (present) , Gastroesophageal reflux (present) , Abnormality of limbs (present) , Clubfoot (present) , Hydrocele testis (present) , High palate (present) , Low-set ears (present) , Irritability (present) , Congenital laryngomalacia (present) , Patent ductus arteriosus (present) , Respiratory distress (present) , Tachypnea (present) , Thoracic hypoplasia (present) , Stridor (present) (less)
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Osteogenesis imperfecta type III
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058347.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000456802, PMID:16705691, PS1_S).The variant … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000456802, PMID:16705691, PS1_S).The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 29150909, 26432670, 26371943, 31299979, PS4_S). A different missense change at the same codon has been reported to be associated with COL1A2 related disorder (PMID:9240878,28116328, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.981, 3CNET: 0.993, PP3_P). A missense variant is a common mechanism associated with Osteogenesis imperfecta (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Increased susceptibility to fractures (present) , Large fontanelles (present)
|
|
Pathogenic
(Jan 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Osteogenesis imperfecta type III
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512407.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4, PM1 moderate, PM2 moderate, PM5, PP3 supporting, PP4 supporting
Geographic origin: Brazil
|
|
Pathogenic
(Jul 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Osteogenesis imperfecta, perinatal lethal
Osteogenesis imperfecta with normal sclerae, dominant form Osteoporosis Ehlers-Danlos syndrome, cardiac valvular type Osteogenesis imperfecta type III Ehlers-danlos syndrome, arthrochalasia type, 2 Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002783179.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Nov 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Osteogenesis imperfecta type I
Ehlers-Danlos syndrome, classic type, 1
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000627290.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL1A2. Glycine residues within the Gly-Xaa-Yaa repeats … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL1A2. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL1A2, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). 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 expected to disrupt COL1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 456802). This missense change has been observed in individuals with osteogenesis imperfecta (PMID: 16705691, 21520333, 22589248, 26371943, 26432670, 29150909; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 358 of the COL1A2 protein (p.Gly358Ser). (less)
|
|
Pathogenic
(Apr 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247411.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Osteogenesis imperfecta, perinatal lethal
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760203.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
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 |
---|---|---|---|---|
Prenatal diagnosis of fetal skeletal dysplasia using targeted next-generation sequencing: an analysis of 30 cases. | Liu Y | Diagnostic pathology | 2019 | PMID: 31299979 |
Genetic analysis of osteogenesis imperfecta in the Palestinian population: molecular screening of 49 affected families. | Essawi O | Molecular genetics & genomic medicine | 2018 | PMID: 29150909 |
Hip Dysplasia in Children With Osteogenesis Imperfecta: Association With Collagen Type I C-Propeptide Mutations. | Kishta W | Journal of pediatric orthopedics | 2017 | PMID: 26371943 |
Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing. | Taillandier A | Molecular genetics and metabolism | 2015 | PMID: 26432670 |
Cardiopulmonary dysfunction in the Osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms. | Thiele F | Human molecular genetics | 2012 | PMID: 22589248 |
LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. | Marini JC | Human mutation | 2007 | PMID: 17078022 |
Mutational spectrum of type I collagen genes in Korean patients with osteogenesis imperfecta. | Lee KS | Human mutation | 2006 | PMID: 16705691 |
Parental mosaicism and autosomal dominant mutations causing structural abnormalities of collagen I are frequent in families with osteogenesis imperfecta type III/IV. | Lund AM | Acta paediatrica (Oslo, Norway : 1992) | 1997 | PMID: 9240878 |
The human type I collagen mutation database. | Dalgleish R | Nucleic acids research | 1997 | PMID: 9016532 |
Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. | Bella J | Science (New York, N.Y.) | 1994 | PMID: 7695699 |
Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence. | Long CG | Biochemistry | 1993 | PMID: 8218237 |
click to load more click to collapse |
Text-mined citations for rs66619856 ...
HelpRecord last updated May 01, 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.