NM_000088.4(COL1A1):c.3235G>A (p.Gly1079Ser) AND Osteogenesis imperfecta type I

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 3, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000018863.36

Allele description [Variation Report for NM_000088.4(COL1A1):c.3235G>A (p.Gly1079Ser)]

NM_000088.4(COL1A1):c.3235G>A (p.Gly1079Ser)

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.3235G>A (p.Gly1079Ser)

Other names:

G901S

HGVS:

NC_000017.11:g.50188122C>T
NG_007400.1:g.18518G>A
NM_000088.4:c.3235G>AMANE SELECT
NP_000079.2:p.Gly1079Ser
NP_000079.2:p.Gly1079Ser
LRG_1t1:c.3235G>A
LRG_1:g.18518G>A
LRG_1p1:p.Gly1079Ser
NC_000017.10:g.48265483C>T
NM_000088.3:c.3235G>A

Protein change:

G1079S; GLY901SER

Links:

OMIM: 120150.0040; dbSNP: rs72654802

NCBI 1000 Genomes Browser:

rs72654802

Molecular consequence:

NM_000088.4:c.3235G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039146	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 1992)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000574618	Department of Medical Sciences, Uppsala University See additional submitters Department of Dental Medicine, Karolinska Institutet	no assertion criteria provided	Pathogenic	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000752555	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 3, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 1634225, 18311573, 21594610, 21667357, 23079818, 26177859, 27509835, 28498836, 28810924, 9016532, 17078022, 7695699, 8218237, 18845533, 19344236, 28492532
SCV002579610	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 29, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	maternal	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

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

Mild dominant osteogenesis imperfecta with intrafamilial variability: the cause is a serine for glycine alpha 1(I) 901 substitution in a type-I collagen gene.

Mottes M, Sangalli A, Valli M, Gomez Lira M, Tenni R, Buttitta P, Pignatti PF, Cetta G.

Hum Genet. 1992 Jul;89(5):480-4.

PubMed [citation]

PMID:: 1634225

See all PubMed Citations (18)

Details of each submission

From OMIM, SCV000039146.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Mottes et al. (1992) identified a GGC (gly) to AGC (ser) transition in codon 901 of the COL1A1 gene in an 8-year-old boy with repeated fractures of both femora. Intramedullar rodding had been performed at the age of 3 years. His mother, 44 years old at the time of his birth, was short (140 cm) and had mild hypoacusis from age 40 and moderate osteoporosis but had never had fractures. The mother was likewise heterozygous for the gly901-to-ser mutation. The mild phenotype was surprising in light of the usual experience that glycine substitutions in the C-terminal region of the collagen triple helix cause lethal OI. The patient was classified as OI type IB on the basis of the absence of dentinogenesis imperfecta (see 166200).

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

From Department of Medical Sciences, Uppsala University, SCV000574618.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752555.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This missense change has been observed in individual(s) with osteogenesis imperfecta (OI) type I and OI types I, III and IV (PMID: 1634225, 18311573, 21594610, 21667357, 23079818, 26177859, 27509835, 28498836, 28810924). 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 replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1079 of the COL1A1 protein (p.Gly1079Ser). ClinVar contains an entry for this variant (Variation ID: 17322). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL1A1. 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 COL1A1, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). Experimental studies have shown that this missense change affects COL1A1 function (PMID: 7695699, 8218237, 18845533, 19344236). 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 COL1A1 protein function.

#	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

From MGZ Medical Genetics Center, SCV002579610.1

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

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

Last Updated: Oct 13, 2024

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