rs67507747

Positions:

• chr17-50194032-C-A
• chr17-50194032-C-G
• chr17-50194032-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.1678G>T​(p.Gly560Cys) variant causes a missense 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. 11/19 in silico tools predict a damaging 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. G560R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.69

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]

COL1A1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a compositionally_biased_region Pro residues (size 23) in uniprot entity CO1A1_HUMAN there are 26 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A1. . Gene score misZ 3.5319 (greater than the threshold 3.09). Trascript score misZ 5.7733 (greater than threshold 3.09). GenCC has associacion of gene with Caffey disease, Ehlers-Danlos/osteogenesis imperfecta syndrome, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, 1, high bone mass osteogenesis imperfecta, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, classic type, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 17-50194032-C-A is Pathogenic according to our data. Variant chr17-50194032-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 526860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50194032-C-A is described in Lovd as [Pathogenic]. Variant chr17-50194032-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1678G>T	p.Gly560Cys	missense_variant	25/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.1480G>T	p.Gly494Cys	missense_variant	22/48		XP_011522643.1
COL1A1	XM_005257058.5	c.1678G>T	p.Gly560Cys	missense_variant	25/49		XP_005257115.2
COL1A1	XM_005257059.5	c.958-1339G>T		intron_variant			XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1678G>T	p.Gly560Cys	missense_variant	25/51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000463440.1	n.68G>T		non_coding_transcript_exon_variant	3/3	2
COL1A1	ENST00000471344.1	n.710G>T		non_coding_transcript_exon_variant	8/8	2
COL1A1	ENST00000476387.1	n.27G>T		non_coding_transcript_exon_variant	1/9	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 30, 2022	ClinVar contains an entry for this variant (Variation ID: 526860). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly560 amino acid residue in COL1A1. Other variant(s) that disrupt this residue have been observed in individuals with COL1A1-related conditions (PMID: 8799376, 17078022, 24668929, 27510842), which suggests that this may be a clinically significant amino acid residue. 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. This missense change has been observed in individual(s) with clinical features of osteogenesis imperfecta (PMID: 17078022, 28378289). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 560 of the COL1A1 protein (p.Gly560Cys). -

COL1A1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2022

The COL1A1 c.1678G>T variant is predicted to result in the amino acid substitution p.Gly560Cys. This variant was reported in individuals with osteogenesis imperfecta (Bardai et al. 2017. PubMed ID: 28378289; Marini et al. 2007. PubMed ID: 17078022; https://databases.lovd.nl/shared/genes/COL1A1). Different missense variants altering the same amino acid residue (p.Gly560Ser, p.Gly560Arg) have also been reported in individuals with osteogenesis imperfecta (for examples see Marini et al. 2007. PubMed ID: 17078022). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jul 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		1.0
MutPred		1.0		Gain of catalytic residue at G560 (P = 0.0495);
MVP		1.0
MPC		0.60
ClinPred		1.0	D
GERP RS		4.4
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

Other links and lift over

dbSNP: rs67507747; hg19: chr17-48271393;