17-50188122-C-T

Position:

• chr17-50188122-C-T

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.3235G>A​(p.Gly1079Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,425,036 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G1079R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: 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]

COL1A1 (HGNC:):

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 chr17-50188122-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 17-50188122-C-T is Pathogenic according to our data. Variant chr17-50188122-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188122-C-T is described in Lovd as [Pathogenic]. Variant chr17-50188122-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.3235G>A	p.Gly1079Ser	missense_variant	44/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.3037G>A	p.Gly1013Ser	missense_variant	41/48		XP_011522643.1
COL1A1	XM_005257058.5	c.2965G>A	p.Gly989Ser	missense_variant	42/49		XP_005257115.2
COL1A1	XM_005257059.5	c.2317G>A	p.Gly773Ser	missense_variant	31/38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.3235G>A	p.Gly1079Ser	missense_variant	44/51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000486572.1	n.433G>A		non_coding_transcript_exon_variant	1/2	3
COL1A1	ENST00000511732.1	n.559G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1425036 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 705964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.16e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 29, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Medical Sciences, Uppsala University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 03, 2023	This missense change has been observed in individual(s) with osteogenesis imperfecta (OI) type I and OI types I, III and IV (PMID: 1634225, 18311573, 21594610, 21667357, 23079818, 26177859, 27509835, 28498836, 28810924). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1079 of the COL1A1 protein (p.Gly1079Ser). ClinVar contains an entry for this variant (Variation ID: 17322). For these reasons, this variant has been classified as Pathogenic. 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). Experimental studies have shown that this missense change affects COL1A1 function (PMID: 7695699, 8218237, 18845533, 19344236). 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1992	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2024	Occurs in the triple helical domain and replaces a glycine in a 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 (PMID: 34007986); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as G901S; This variant is associated with the following publications: (PMID: 37270749, 35909573, 27060301, 21280025, 23079818, 27509835, 26177859, 21594610, 18218237, 18311573, 28498836, 21667357, 28810924, 25944380, 31414283, 34358384, 32166892, Tian2020[Article], 31429852, 35456387, 37859607, 17078022, 15241796, 30715774, 18845533, 34007986, 1634225, 1886404) -

Osteogenesis imperfecta type I;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PP2+PS3_Moderate+PS4+PP1_Strong+PP4+PM6_Supporting -

COL1A1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2023

The COL1A1 c.3235G>A variant is predicted to result in the amino acid substitution p.Gly1079Ser. This variant was reported in multiple individuals with osteogenesis imperfecta (OI), or OI/Danlos Overlap syndrome (for examples: reported as p.Gly901Ser in Mottes. 1992. PubMed ID: 1634225; Moraes. 2012. PubMed ID: 23079818; de novo in Morabito. 2022. PubMed ID: 35456387). The p.Gly1079 amino acid is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Marini et al. 2007. PubMed ID: 17078022).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	0.80
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Vest4		0.98
MutPred		0.98		Gain of glycosylation at G1079 (P = 7e-04);
MVP		0.99
MPC		0.56
ClinPred		1.0	D
GERP RS		5.3
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: rs72654802; hg19: chr17-48265483;