NM_000088.4:c.3897C>G

Variant names:

• chr17-50186425-G-C
• rs34940368
• NM_000088.4:c.3897C>G

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.3897C>G​(p.Cys1299Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1299R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.772

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 strand (size 3) in uniprot entity CO1A1_HUMAN there are 5 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 chr17-50186427-A-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in the COL1A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. Gene score misZ: 3.5319 (above the threshold of 3.09). Trascript score misZ: 5.7733 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.995
• PP5: Variant 17-50186425-G-C is Pathogenic according to our data. Variant chr17-50186425-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 425627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50186425-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.3897C>G	p.Cys1299Trp	missense_variant	Exon 49 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.3699C>G	p.Cys1233Trp	missense_variant	Exon 46 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.3627C>G	p.Cys1209Trp	missense_variant	Exon 47 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.2979C>G	p.Cys993Trp	missense_variant	Exon 36 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.3897C>G	p.Cys1299Trp	missense_variant	Exon 49 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000510710.3	n.566C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COL1A1-related disorder Pathogenic:1

Aug 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL1A1 c.3897C>G variant is predicted to result in the amino acid substitution p.Cys1299Trp. This variant was reported in multiple individuals with osteogenesis imperfecta (Pace et al. 2001. PubMed ID: 11432962; Table S1, Lindahl et al. 2015. PubMed ID: 26177859; Aftab et al. 2013. PubMed ID: 24616757). Functional studies support the pathogenicity of this variant (Li et al. 2021. PubMed ID: 33674390). 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. -

Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1

-

Department of Medical Sciences, Uppsala University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Osteogenesis imperfecta type I Pathogenic:1

May 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 1299 of the COL1A1 protein (p.Cys1299Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 11432962, 26177859; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 425627). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL1A1 protein function. Experimental studies have shown that this missense change affects COL1A1 function (PMID: 11432962). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.58	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.96
MutPred		0.97		Gain of catalytic residue at P1302 (P = 0.0256);
MVP		0.98
MPC		0.96
ClinPred		1.0	D
GERP RS		-0.31
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34940368; hg19: chr17-48263786;