NM_000088.4(COL1A1):c.1004G>A (p.Gly335Asp) AND Osteogenesis imperfecta, perinatal lethal

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 17, 2020
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:: RCV001263481.1

Allele description [Variation Report for NM_000088.4(COL1A1):c.1004G>A (p.Gly335Asp)]

NM_000088.4(COL1A1):c.1004G>A (p.Gly335Asp)

Gene:

COL1A1:collagen type I alpha 1 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.33

Genomic location:

Preferred name:

NM_000088.4(COL1A1):c.1004G>A (p.Gly335Asp)

HGVS:

NC_000017.11:g.50195975C>T
NG_007400.1:g.10665G>A
NM_000088.4:c.1004G>AMANE SELECT
NP_000079.2:p.Gly335Asp
LRG_1t1:c.1004G>A
LRG_1:g.10665G>A
NC_000017.10:g.48273336C>T
NM_000088.3:c.1004G>A

Protein change:

G335D

Links:

dbSNP: rs1907549643

NCBI 1000 Genomes Browser:

rs1907549643

Molecular consequence:

NM_000088.4:c.1004G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Osteogenesis imperfecta, perinatal lethal (OI2)
Synonyms:: OI, TYPE II; Osteogenesis imperfecta congenita perinatal lethal form; Osteogenesis imperfecta congenita; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008147; MedGen: C0268358; OMIM: 166210

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001441563	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 17, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20301472, 21239989, 31349857, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001441563

Johns Hopkins Genomics, Johns Hopkins University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 17, 2020)

germline

clinical testing

PubMed (4)
[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

COL1A1/2 Osteogenesis Imperfecta.

Steiner RD, Basel D.

2005 Jan 28 [updated 2024 Mar 14]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301472

Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance.

Pyott SM, Pepin MG, Schwarze U, Yang K, Smith G, Byers PH.

Genet Med. 2011 Feb;13(2):125-30. doi: 10.1097/GIM.0b013e318202e0f6.

PubMed [citation]

PMID:: 21239989

See all PubMed Citations (4)

Details of each submission

From Johns Hopkins Genomics, Johns Hopkins University, SCV001441563.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This COL1A1 variant is absent in a large population dataset and has not been reported previously in the literature to our knowledge. This variant was detected in the paternal sample used for analysis. The reduced alternate allele fraction and absence of COL1A1-associated phenotypes suggest c.1004G>A is mosaic in the patient father (see Notes for more information). Three bioinformatics tools predict this variant would be damaging. This variant disrupts a strongly conserved glycine residue in the canonical G-X-Y repeats of the triple helix domain, which are required for stability and structure of the protein. Missense variants in nearby glycine residues have been reported in individuals with osteogenesis imperfecta supporting their functional significance. This variant is not predicted to affect normal exon 16 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1004G>A to be likely 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 1, 2024

ClinVar

Relating variation to medicine