chr17-50188776-C-A

Position:

• chr17-50188776-C-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000088.4(COL1A1):​c.3065G>T​(p.Gly1022Val) 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. G1022A) 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:4
• Conservation: PhyloP100: 6.08

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-50188776-C-G is described in Lovd as [Pathogenic].
• 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, 0.996
• PP5: Variant 17-50188776-C-A is Pathogenic according to our data. Variant chr17-50188776-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188776-C-A is described in Lovd as [Pathogenic]. Variant chr17-50188776-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.3065G>T	p.Gly1022Val	missense_variant	42/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.2867G>T	p.Gly956Val	missense_variant	39/48		XP_011522643.1
COL1A1	XM_005257058.5	c.2795G>T	p.Gly932Val	missense_variant	40/49		XP_005257115.2
COL1A1	XM_005257059.5	c.2147G>T	p.Gly716Val	missense_variant	29/38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.3065G>T	p.Gly1022Val	missense_variant	42/51	1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000511732.1	n.9G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2023	Reported previously as G844V in multiple patients with osteogenesis imperfecta type II in published literature (Korkko et al., 1997; Marini et al., 2007); 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, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18996919, 30942118, 17078022, 9067755) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 18, 2018	The COL1A1 c.3065G>T; p.Gly1022Val variant (rs67771061), also known as Gly844Val for legacy nomenclature, has been described in several individuals affected with osteogenesis imperfect (OI) type II (Bodian 2009, Korkko 1997, Marini 2007). It is reported as pathogenic by at least one laboratory in ClinVar (Variation ID: 420061) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the repeating Gly-X-Y sequence motif of the collagen triple helix and is predicted to impair collagen function (Ben Amor 2011). Additional variants at this codon (p.Gly1022Ser, p.Gly1022Ala) have been reported in individuals with OI types I/IV and III and are considered pathogenic (Chen 2012, Marini 2007, Obafemi 2008). Based on available information, this variant is considered pathogenic. Pathogenic germline COL1A1 variants are inherited in an autosomal dominant manner, and are associated with osteogenesis imperfecta type I (MIM: 166200), osteogenesis imperfecta type II (MIM: 166210), osteogenesis imperfecta type III (MIM: 259420) and osteogenesis imperfecta type IV (MIM: 166220). References: Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Bodian DL et al. Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype-phenotype relationships. Hum Mol Genet. 2009 Feb 1;18(3):463-71. Chen C et al. Identification of a missense mutation of c.3064G>A, Gly1022Ser in exon 43 of COL1A1 gene in a girl with osteogenesis imperfecta type III. Genet Couns. 2012;23(3):359-65. Korkko J et al. Two new recurrent nucleotide mutations in the COL1A1 gene in four patients with osteogenesis imperfecta: about one-fifth are recurrent. Hum Mutat. 1997;9(2):148-56. Marini JC et al. Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat. 2007 Mar;28(3):209-21. Obafemi A et al. Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation. Am J Med Genet A. 2008 Nov 1;146A(21):2725-32. -

Osteogenesis imperfecta Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2019

- -

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.029	D
Vest4		0.98
MutPred		1.0		Loss of catalytic residue at P1018 (P = 0.0741);
MVP		0.99
MPC		0.70
ClinPred		1.0	D
GERP RS		4.0
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: rs67771061; hg19: chr17-48266137;