17-50188131-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.3226G>A(p.Gly1076Ser) 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. 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. G1076C) 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:8
• Conservation: PhyloP100: 7.71

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 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 chr17-50188131-C-A is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, COL1A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 17-50188131-C-T is Pathogenic according to our data. Variant chr17-50188131-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 425618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188131-C-T is described in Lovd as [Pathogenic]. Variant chr17-50188131-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.3226G>A	p.Gly1076Ser	missense_variant	44/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.3028G>A	p.Gly1010Ser	missense_variant	41/48
COL1A1	XM_005257058.5	c.2956G>A	p.Gly986Ser	missense_variant	42/49
COL1A1	XM_005257059.5	c.2308G>A	p.Gly770Ser	missense_variant	31/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.3226G>A	p.Gly1076Ser	missense_variant	44/51	1	NM_000088.4	P1
COL1A1	ENST00000486572.1	n.424G>A		non_coding_transcript_exon_variant	1/2	3
COL1A1	ENST00000511732.1	n.550G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2022	Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27510842, 29499418, 31994750, 8218237, 32034735, 25944380, 21667357, 29150909, 19344236, 9016532, 17078022, 7695699, 25086671, 27519266, 9101304, 28116328, 29807018, 24863959, 33939306, 24077912, 27535533) -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 30, 2019	The COL1A1 c.3226G>A; p.Gly1076Ser variant (rs67394386) is reported in the literature in multiple individuals who were affected with osteogenesis imperfect, and this variant was de novo in at least two of these individuals (Lindahl 2015, Lund 1997, Malmgren 2017, and Mrosk 2018). This variant is reported in ClinVar (Variation ID: 425618), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This codon is located in a triple helix repeat domain, and glycine substitutions are the most frequent pathogenic alterations in this region (Ben Amor 2011). The glycine at codon 1076 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. -

Osteogenesis imperfecta type III Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Medical Sciences, Uppsala University	-	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jan 10, 2019	ACMG codes: PS2, PS4, PM2, PP3, PP4, PP5 -

COL1A1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2023

The COL1A1 c.3226G>A variant is predicted to result in the amino acid substitution p.Gly1076Ser. This variant (legacy nomenclature p.Gly898Ser) was reported in multiple individuals with osteogenesis imperfecta, being de novo when parental testing was performed (Lund. 1997. PubMed ID: 9101304; Table S2, Bowling. 2021. PubMed ID: 34930662; Higuchi. 2021. PubMed ID: 33939306; Table S2, Mei. 2022. PubMed ID: 35909573; Han. 2020. PubMed ID: 31994750). This variant is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Residues 179-1192, https://www.uniprot.org/; Legacy nomenclature in Marini. 2007. PubMed ID: 17078022 indicates amino acids 1-1012; Symoens. 2014. PubMed ID: 25146735). 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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 24, 2019

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1076 of the COL1A1 protein (p.Gly1076Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 9101304, 26177859, 29150909, 29499418). In at least one individual the variant was observed to be de novo. This variant is also known as Gly898Ser. ClinVar contains an entry for this variant (Variation ID: 425618). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Vest4		0.94
MutPred		0.97		Gain of glycosylation at G1076 (P = 0.0011);
MVP		0.99
MPC		0.56
ClinPred		0.99	D
GERP RS		5.1
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: rs67394386; hg19: chr17-48265492;