NM_000089.4(COL1A2):c.794G>A (p.Gly265Asp) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 24, 2021
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:: RCV001851298.4

Allele description [Variation Report for NM_000089.4(COL1A2):c.794G>A (p.Gly265Asp)]

NM_000089.4(COL1A2):c.794G>A (p.Gly265Asp)

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.794G>A (p.Gly265Asp)

HGVS:

NC_000007.14:g.94409323G>A
NG_007405.1:g.19763G>A
NM_000089.4:c.794G>AMANE SELECT
NP_000080.2:p.Gly265Asp
NP_000080.2:p.Gly265Asp
LRG_2t1:c.794G>A
LRG_2:g.19763G>A
LRG_2p1:p.Gly265Asp
NC_000007.13:g.94038635G>A
NM_000089.3:c.794G>A

Protein change:

G265D

Links:

dbSNP: rs72656386

NCBI 1000 Genomes Browser:

rs72656386

Molecular consequence:

NM_000089.4:c.794G>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
SCV002231903	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 24, 2021)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9240878, 25944380, 27509835, 7695699, 8218237, 19344236, 9016532, 17078022, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002231903

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 24, 2021)

germline

clinical testing

PubMed (9)
[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

Parental mosaicism and autosomal dominant mutations causing structural abnormalities of collagen I are frequent in families with osteogenesis imperfecta type III/IV.

Lund AM, Nicholls AC, Schwartz M, Skovby F.

Acta Paediatr. 1997 Jul;86(7):711-8.

PubMed [citation]

PMID:: 9240878

Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta.

Lindahl K, Åström E, Rubin CJ, Grigelioniene G, Malmgren B, Ljunggren Ö, Kindmark A.

Eur J Hum Genet. 2015 Aug;23(8):1042-50. doi: 10.1038/ejhg.2015.81. Epub 2015 May 6. Erratum in: Eur J Hum Genet. 2015 Aug;23(8):1112. doi: 10.1038/ejhg.2015.129.

PubMed [citation]

PMID:: 25944380
PMCID:: PMC4795106

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002231903.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 425661). This variant is also known as p.Gly175Asp. This missense change has been observed in individual(s) with autosomal dominant osteogenesis imperfecta (PMID: 9240878, 25944380, 27509835). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 265 of the COL1A2 protein (p.Gly265Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. 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: Sep 29, 2024

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