NM_000089.4(COL1A2):c.3971G>A (p.Trp1324Ter) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 24, 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:: RCV001922511.3

Allele description [Variation Report for NM_000089.4(COL1A2):c.3971G>A (p.Trp1324Ter)]

NM_000089.4(COL1A2):c.3971G>A (p.Trp1324Ter)

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.3971G>A (p.Trp1324Ter)

HGVS:

NC_000007.14:g.94430263G>A
NG_007405.1:g.40703G>A
NM_000089.4:c.3971G>AMANE SELECT
NP_000080.2:p.Trp1324Ter
LRG_2:g.40703G>A
NC_000007.13:g.94059575G>A

Protein change:

W1324*

Links:

dbSNP: rs2115969692

NCBI 1000 Genomes Browser:

rs2115969692

Molecular consequence:

NM_000089.4:c.3971G>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV002167954	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Apr 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25146735, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002167954

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Apr 24, 2023)

germline

clinical testing

PubMed (2)
[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

Type I procollagen C-propeptide defects: study of genotype-phenotype correlation and predictive role of crystal structure.

Symoens S, Hulmes DJ, Bourhis JM, Coucke PJ, De Paepe A, Malfait F.

Hum Mutat. 2014 Nov;35(11):1330-41. doi: 10.1002/humu.22677. Epub 2014 Oct 18.

PubMed [citation]

PMID:: 25146735

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002167954.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1398213). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal dominant osteogenesis imperfecta (PMID: 25146735; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp1324*) in the COL1A2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the COL1A2 protein.

#	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: Mar 5, 2024

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