NM_000089.4(COL1A2):c.298G>A (p.Gly100Ser) AND COL1A2-related disorder

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 19, 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:: RCV004527693.2

Allele description [Variation Report for NM_000089.4(COL1A2):c.298G>A (p.Gly100Ser)]

NM_000089.4(COL1A2):c.298G>A (p.Gly100Ser)

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.298G>A (p.Gly100Ser)

HGVS:

NC_000007.14:g.94404574G>A
NG_007405.1:g.15014G>A
NM_000089.4:c.298G>AMANE SELECT
NP_000080.2:p.Gly100Ser
NP_000080.2:p.Gly100Ser
LRG_2t1:c.298G>A
LRG_2:g.15014G>A
LRG_2p1:p.Gly100Ser
NC_000007.13:g.94033886G>A
NM_000089.3:c.298G>A

Protein change:

G100S

Links:

dbSNP: rs1410254723

NCBI 1000 Genomes Browser:

rs1410254723

Molecular consequence:

NM_000089.4:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: COL1A2-related disorder
Synonyms:: COL1A2-related condition; COL1A2-Related Disorders
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001786643	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (Jan 19, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31039433, 31794058 Citation Link,
SCV005349885	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Likely pathogenic (Mar 11, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001786643

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Likely pathogenic
(Jan 19, 2021)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV005349885

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Likely pathogenic
(Mar 11, 2024)

germline

clinical testing

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mendelian bone fragility disorders.

Robinson ME, Rauch F.

Bone. 2019 Sep;126:11-17. doi: 10.1016/j.bone.2019.04.021. Epub 2019 Apr 27. Review.

PubMed [citation]

PMID:: 31039433

Morlino S, Micale L, Ritelli M, Rohrbach M, Zoppi N, Vandersteen A, Mackay S, Agolini E, Cocciadiferro D, Sasaki E, Madeo A, Ferraris A, Reardon W, Di Rocco M, Novelli A, Grammatico P, Malfait F, Mazza T, Hakim A, Giunta C, Colombi M, Castori M.

Clin Genet. 2020 Mar;97(3):396-406. doi: 10.1111/cge.13683. Epub 2019 Dec 12.

PubMed [citation]

PMID:: 31794058

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001786643.1

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

Description

The COL1A2 c.298G>A (p.Gly100Ser) variant is a missense variant. A literature search was conducted for the gene, cDNA change, and amino acid change. No publications were found based on this search, but there is an entry in ClinVar for this variant, in which the p.Gly100Ser variant is reported to have been observed in individuals with clinical features of osteogenesis imperfecta (ClinVar variation ID: 526897). The p.Gly100Ser variant is reported at a frequency of 0.000007 in the Total population of the Genome Aggregation Database, though this is based on two alleles in region of good sequence coverage so the variant is presumed rare. This variant affects a glycine residue within the Gly-Xaa-Yaa motifs of the highly conserved triple helix domain that play a critical role in protein structure and stability; this variant type is a known cause of disease (Robinson and Rauch 2019; Morlino et al. 2020). The Gly100Ser variant also falls within the cluster of glycine substitution variants clustering around the procollagen N-proteinase cleavage site that have been specifically linked to osteogenesis imperfecta/Ehlers-Danlos overlap syndrome (Morlino et al. 2020). Multiple in silico tools consistently predict a functional effect of this variant, but these predictions have not been assessed experimentally. Based on the collective evidence, the p.Gly100Ser variant is classified as likely pathogenic for COL1A2-related disorders.

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

From PreventionGenetics, part of Exact Sciences, SCV005349885.1

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

Description

The COL1A2 c.298G>A variant is predicted to result in the amino acid substitution p.Gly100Ser. This variant was reported in an individual with Osteogenesis imperfecta/Ehlers-Danlos syndrome (Case 6 in Table 1, Venable et al. 2023. PubMed ID: 36896471). In ClinVar, this variant is interpreted as likely pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/526897/). This This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-94033886-G-A). The p.Gly100Ser residue is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Marini et al. 2007. PubMed ID: 17078022). This variant is interpreted as 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: Nov 3, 2024

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