chr7-94409367-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2PP3_StrongPP5_Very_Strong

The NM_000089.4(COL1A2):​c.838G>A​(p.Gly280Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,028 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

COL1A2
NM_000089.4 missense

Scores

12
6
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 9.84
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A2. . Gene score misZ 2.1491 (greater than the threshold 3.09). Trascript score misZ 3.5344 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos/osteogenesis imperfecta syndrome, Ehlers-Danlos syndrome, cardiac valvular type, ehlers-danlos syndrome, arthrochalasia type, 2, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, high bone mass osteogenesis imperfecta, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, osteogenesis imperfecta type 4, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 7-94409367-G-A is Pathogenic according to our data. Variant chr7-94409367-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 35957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94409367-G-A is described in Lovd as [Pathogenic]. Variant chr7-94409367-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-94409367-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL1A2NM_000089.4 linkuse as main transcriptc.838G>A p.Gly280Ser missense_variant 17/52 ENST00000297268.11 NP_000080.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL1A2ENST00000297268.11 linkuse as main transcriptc.838G>A p.Gly280Ser missense_variant 17/521 NM_000089.4 ENSP00000297268 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251480
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461888
Hom.:
0
Cov.:
32
AF XY:
0.00000688
AC XY:
5
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:5
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsNov 17, 2014- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJul 23, 2019- -
Likely pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 03, 2023Identified in multiple other unrelated patients with OI types I and IV in published literature (Roschger et al., 2008; Zhang et al., 2012; Rauch et al., 2014; Maioli et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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 et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25086671, 17078022, 30886339, 28378289, 21667357, 10807697, 31414283, 26177859, 18311573, 34007986, 35909573, 37758163) -
Osteogenesis imperfecta, perinatal lethal Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMay 25, 2022Criteria applied: PM1_STR,PS4_MOD,PM5,PP3,PP4 -
Pathogenic, criteria provided, single submitterclinical testingFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsApr 20, 2024The identified heterozygous missense substitution (p.Gly280Ser) lies in exon 17 of the COL1A2 gene and alters a highly conserved residue in the protein. The identified variant has been previously reported in patients affected with OI and increased susceptibility to fractures. The variant is predicted to be damaging by 5 (FATHMM, LRT, Mutation Assessor, Mutation Taster and SIFT) out of 5 in silico missense prediction tools. In summary, the variant meets our criteria to be classified as pathogenic. -
Osteogenesis imperfecta Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testing;curationWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 18, 2011- -
COL1A2-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesAug 27, 2024The COL1A2 c.838G>A variant is predicted to result in the amino acid substitution p.Gly280Ser. This variant has been reported to be pathogenic for osteogenesis Imperfecta (Table S4, Mei et al. 2022. PubMed ID: 35909573; Type IV or Type I, Marini et al. 2007.PubMed ID: 17078022). Different variants affecting the same amino acid (p.Gly280Cys and p.Gly280Val) were reported to be pathogenic (Ho Duy et al. 2016. PubMed ID: 27519266; reported as p.Gly190Val, Obafemi. et al. 2008. PubMed ID: 18798308). The p.Gly280 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 reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterFeb 21, 2022- -
Ehlers-danlos syndrome, arthrochalasia type, 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 29, 2024- -
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 23, 2023This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 280 of the COL1A2 protein (p.Gly280Ser). This variant is present in population databases (rs72656387, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant osteogenesis imperfecta (PMID: 17078022, 21667357, 26177859, 28378289). ClinVar contains an entry for this variant (Variation ID: 35957). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. -
Increased susceptibility to fractures Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMay 25, 2022_x000D_ Criteria applied: PM1_STR, PS4_MOD, PM5, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.78
D;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Pathogenic
0.81
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.9
H;.
MutationTaster
Benign
1.0
A
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-5.0
D;.
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.014
D;D
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.99
Loss of catalytic residue at G280 (P = 0.0055);.;
MVP
0.99
MPC
0.26
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.80
gMVP
1.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72656387; hg19: chr7-94038679; API