rs72659319

chr7-94426459-G-Achr7-94426459-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000089.4(COL1A2):c.3034G>A(p.Gly1012Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. G1012R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COL1A2 NM_000089.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 10.0

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 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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 chr7-94426459-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 17235.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 7-94426459-G-A is Pathogenic according to our data. Variant chr7-94426459-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94426459-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4	c.3034G>A	p.Gly1012Ser	missense_variant	46/52	ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11	c.3034G>A	p.Gly1012Ser	missense_variant	46/52	1	NM_000089.4	P1
COL1A2	ENST00000478215.1	n.593G>A		non_coding_transcript_exon_variant	4/4	3
COL1A2	ENST00000481570.5	n.3007G>A		non_coding_transcript_exon_variant	5/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454186 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2021	Occurs in the triple helical domain and replaces a glycine in a canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (Jovanovic M et al. 2021); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16705691, 25944380, 29150909, 8094076, 17078022, 8401517, 9367795, 27519266, 15241796, 29807018, 30984112, 30692697, 33939306, 30715774, 31414283, 25450603) -

Osteogenesis imperfecta Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Baylor Genetics

Nov 18, 2018

- -

Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Medical Sciences, Uppsala University

-

- -

Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 25, 2023

This variant disrupts the triple helix domain of COL1A2. 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 COL1A2, variants affecting these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). 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 COL1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 216908). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta (PMID: 8094076, 16705691, 22589248, 25450603, 27519266). 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 1012 of the COL1A2 protein (p.Gly1012Ser). For these reasons, this variant has been classified as Pathogenic. -

Osteogenesis imperfecta, perinatal lethal Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Sep 04, 2017

The mutation of c.3034G>A p.(Gly1012Ser) is de novo. -

Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Nov 05, 2013

- -

Postmenopausal osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4303789:Ehlers-Danlos syndrome, cardiac valvular type;CN293783:Ehlers-danlos syndrome, arthrochalasia type, 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.4	D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.99		Gain of phosphorylation at G1012 (P = 0.0066);.;
MVP		0.99
MPC		0.21
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs72659319; hg19: chr7-94055771; COSMIC: COSV51957475; COSMIC: COSV51957475;