rs1555574143

Positions:

• chr17-50195601-C-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The ENST00000225964.10(COL1A1):​c.1121G>C​(p.Gly374Ala) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 ENST00000225964.10 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91

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 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in ENST00000225964.10
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.993
• PP5: Variant 17-50195601-C-G is Pathogenic according to our data. Variant chr17-50195601-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 447137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50195601-C-G is described in Lovd as [Pathogenic]. Variant chr17-50195601-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1121G>C	p.Gly374Ala	missense_variant	17/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.1121G>C	p.Gly374Ala	missense_variant	17/49		XP_005257115.2
COL1A1	XM_005257059.5	c.957+713G>C		intron_variant			XP_005257116.2
COL1A1	XM_011524341.2	c.958-123G>C		intron_variant			XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1121G>C	p.Gly374Ala	missense_variant	17/51	1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000471344.1	n.65G>C		non_coding_transcript_exon_variant	1/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 27, 2016

- -

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2022

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: 447137). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 27509835, 27748872). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 374 of the COL1A1 protein (p.Gly374Ala). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Vest4		0.98
MutPred		0.98		Loss of catalytic residue at G374 (P = 0.0077);
MVP		0.98
MPC		0.61
ClinPred		1.0	D
GERP RS		4.6
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1555574143; hg19: chr17-48272962; COSMIC: COSV56803033; COSMIC: COSV56803033;