rs72667029

Positions:

• chr17-50197992-C-A

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.599G>T​(p.Gly200Val) 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. G200S) has been classified as 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:3
• Conservation: PhyloP100: 5.99

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 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 chr17-50197993-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2780397.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, 0.993
• PP5: Variant 17-50197992-C-A is Pathogenic according to our data. Variant chr17-50197992-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 526854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50197992-C-A is described in Lovd as [Pathogenic]. Variant chr17-50197992-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.599G>T	p.Gly200Val	missense_variant	8/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.599G>T	p.Gly200Val	missense_variant	8/48
COL1A1	XM_005257058.5	c.599G>T	p.Gly200Val	missense_variant	8/49
COL1A1	XM_005257059.5	c.599G>T	p.Gly200Val	missense_variant	8/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.599G>T	p.Gly200Val	missense_variant	8/51	1	NM_000088.4	P1
COL1A1	ENST00000495677.1	n.326G>T		non_coding_transcript_exon_variant	3/8	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, arthrochalasia type Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.599G>T(p.Gly200Val) variant in COL1A1 gene has been reported previously in heterozygous state in individual(s) affected with COL1A1-related disorders (Balasubramanian M, et. al., 2015). The p.Gly200Val variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Gly200Val in COL1A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 200 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2019

- -

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2021

This variant has been reported in individuals affected with osteogenesis imperfecta (PMID: 18670065, 25436829). For these reasons, this variant has been classified as Pathogenic. 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 9016532, 17078022) compared to the general population (ExAC). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 200 of the COL1A1 protein (p.Gly200Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.99
Sift	Benign	0.034	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.89
MutPred		1.0		Gain of sheet (P = 0.0266);
MVP		0.98
MPC		0.70
ClinPred		1.0	D
GERP RS		4.4
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72667029; hg19: chr17-48275353;