NM_000089.4(COL1A2):c.910G>A (p.Gly304Ser) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 7, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002240729.13

Allele description [Variation Report for NM_000089.4(COL1A2):c.910G>A (p.Gly304Ser)]

NM_000089.4(COL1A2):c.910G>A (p.Gly304Ser)

Gene:

COL1A2:collagen type I alpha 2 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q21.3

Genomic location:

Preferred name:

NM_000089.4(COL1A2):c.910G>A (p.Gly304Ser)

HGVS:

NC_000007.14:g.94409582G>A
NG_007405.1:g.20022G>A
NM_000089.4:c.910G>AMANE SELECT
NP_000080.2:p.Gly304Ser
LRG_2t1:c.910G>A
LRG_2:g.20022G>A
NC_000007.13:g.94038894G>A
NM_000089.3:c.910G>A

Protein change:

G304S

Links:

dbSNP: rs1054264002

NCBI 1000 Genomes Browser:

rs1054264002

Molecular consequence:

NM_000089.4:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Osteogenesis imperfecta type I (OI1)
Synonyms:: OI, TYPE I; Osteogenesis imperfecta type 1; OI type 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008146; MedGen: C0023931; Orphanet: 666; OMIM: 166200

Name:: Ehlers-Danlos syndrome, classic type, 1 (EDSCL1)
Synonyms:: EHLERS-DANLOS SYNDROME, GRAVIS TYPE; EHLERS-DANLOS SYNDROME, SEVERE CLASSIC TYPE; Ehlers-Danlos syndrome, type 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0019567; MedGen: C0268335; OMIM: 130000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001577887	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 7, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 30886339, 7695699, 8218237, 19344236, 9016532, 17078022, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001577887

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 7, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-phenotype correlation study in 364 osteogenesis imperfecta Italian patients.

Maioli M, Gnoli M, Boarini M, Tremosini M, Zambrano A, Pedrini E, Mordenti M, Corsini S, D'Eufemia P, Versacci P, Celli M, Sangiorgi L.

Eur J Hum Genet. 2019 Jul;27(7):1090-1100. doi: 10.1038/s41431-019-0373-x. Epub 2019 Mar 18.

PubMed [citation]

PMID:: 30886339
PMCID:: PMC6777444

Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution.

Bella J, Eaton M, Brodsky B, Berman HM.

Science. 1994 Oct 7;266(5182):75-81.

PubMed [citation]

PMID:: 7695699

See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001577887.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 304 of the COL1A2 protein (p.Gly304Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant osteogenesis imperfecta (PMID: 30886339). ClinVar contains an entry for this variant (Variation ID: 870113). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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