rs1114167416

chr7-94404694-G-Achr7-94404694-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000089.4(COL1A2):c.326G>A(p.Gly109Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G109V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A2 NM_000089.4 missense, splice_region
• Scores: Splicing: ADA: 0.06270
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.60

Genes affected

COL1A2 (HGNC:2198): (collagen type I alpha 2 chain) This gene encodes the pro-alpha2 chain of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000089.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-94404693-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2950794.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, COL1A2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 7-94404694-G-A is Pathogenic according to our data. Variant chr7-94404694-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 425658.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4	c.326G>A	p.Gly109Asp	missense_variant, splice_region_variant	8/52	ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11	c.326G>A	p.Gly109Asp	missense_variant, splice_region_variant	8/52	1	NM_000089.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 29, 2021

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Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2019

The p.G109D variant (also known as c.326G>A), located in coding exon 8 of the COL1A2 gene, results from a G to A substitution at nucleotide position 326. The glycine at codon 109 is replaced by aspartic acid, an amino acid with similar properties. The majority of pathogenic mutations identified to date in COL1A2 have involved the substitution of another amino acid for glycine within the triple-helical domain (Dagleish R. Nucleic Acids Res. 1997 Jan 1;25(1):181-7; Marini JC et al. Hum Mutat. 2007 Mar;28(3):209-21; Bardai G et al. Osteoporos Int 2016 Dec;27(12):3607-3613). This particular glycine substitution has been reported in several patients with osteogenesis imperfecta and Ehlers-Danlos overlap syndrome (Malfait F et al. Orphanet J Rare Dis, 2013 May;8:78; Malmgren B et al. Oral Dis, 2017 Jan;23:42-49). Functional studies in patient fibroblasts suggest that this alteration results in delayed processing of procollagen I into the mature protein (Malfait F et al. Orphanet J Rare Dis, 2013 May;8:78). Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif in the COL1A2 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Medical Sciences, Uppsala University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		1.0		Loss of catalytic residue at G109 (P = 0.1542);.;
MVP		0.99
MPC		0.33
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.84
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.063
dbscSNV1_RF	Benign	0.25
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1114167416; hg19: chr7-94034006;