rs1114167408

Positions:

• chr17-50198186-C-T

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_000088.4(COL1A1):​c.563G>A​(p.Gly188Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G188C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.17

Genes affected

COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains 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 VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two 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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000088.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-50198187-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1992427.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, COL1A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 17-50198186-C-T is Pathogenic according to our data. Variant chr17-50198186-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 425634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50198186-C-T is described in Lovd as [Pathogenic]. Variant chr17-50198186-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.563G>A	p.Gly188Asp	missense_variant	7/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.563G>A	p.Gly188Asp	missense_variant	7/48
COL1A1	XM_005257058.5	c.563G>A	p.Gly188Asp	missense_variant	7/49
COL1A1	XM_005257059.5	c.563G>A	p.Gly188Asp	missense_variant	7/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.563G>A	p.Gly188Asp	missense_variant	7/51	1	NM_000088.4	P1
COL1A1	ENST00000495677.1	n.290G>A		non_coding_transcript_exon_variant	2/8	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 24, 2022	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). 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. ClinVar contains an entry for this variant (Variation ID: 425634). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 27510842). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 188 of the COL1A1 protein (p.Gly188Asp). -
Pathogenic, no assertion criteria provided	clinical testing	Department of Medical Sciences, Uppsala University	-	- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 10, 2020

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2019

The p.G188D variant (also known as c.563G>A), located in coding exon 7 of the COL1A1 gene, results from a G to A substitution at nucleotide position 563. The glycine at codon 188 is replaced by aspartic acid, an amino acid with similar properties. The majority of pathogenic mutations identified to date in COL1A1 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 osteogenesis imperfecta cohorts (Malfait F et al. Orphanet J Rare Dis, 2013 May;8:78; Lindahl K et al. Eur. J. Hum. Genet., 2015 Aug;23:1042-50). 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 COL1A1 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). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Vest4		1.0
MutPred		1.0		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.99
MPC		0.73
ClinPred		1.0	D
GERP RS		5.1
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: rs1114167408; hg19: chr17-48275547;