rs66523073

Positions:

• chr17-50188777-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000088.4(COL1A1):​c.3064G>A​(p.Gly1022Ser) 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 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, single submitter P:2
• Conservation: PhyloP100: 4.99

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 11 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, 0.994
• PP5: Variant 17-50188777-C-T is Pathogenic according to our data. Variant chr17-50188777-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17296.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-50188777-C-T is described in Lovd as [Pathogenic]. Variant chr17-50188777-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.3064G>A	p.Gly1022Ser	missense_variant	42/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.2866G>A	p.Gly956Ser	missense_variant	39/48		XP_011522643.1
COL1A1	XM_005257058.5	c.2794G>A	p.Gly932Ser	missense_variant	40/49		XP_005257115.2
COL1A1	XM_005257059.5	c.2146G>A	p.Gly716Ser	missense_variant	29/38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.3064G>A	p.Gly1022Ser	missense_variant	42/51	1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000511732.1	n.8G>A		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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type III Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 25, 1989

- -

COL1A1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2023

The COL1A1 c.3064G>A variant is predicted to result in the amino acid substitution p.Gly1022Ser. This variant has been reported in several individuals with osteogenesis imperfecta (Reported as Gly844Ser in Pack et al 1989. PubMed ID: 2511192; Chen CP et al 2012. PubMed ID: 23072183; Supp. Table 1, Patient PUMC-208 in Li L et al 2019. PubMed ID: 30715774). 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 et al. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Vest4		0.88
MutPred		0.99		Gain of phosphorylation at G1022 (P = 0.0039);
MVP		0.99
MPC		0.56
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: rs66523073; hg19: chr17-48266138;