17-50191805-C-T

Position:

• chr17-50191805-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.2110G>A​(p.Gly704Ser) 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. 11/19 in silico tools predict a damaging 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. G704C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.87

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 1 benign, 3 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 chr17-50191805-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 17288.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, COL1A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 17-50191805-C-T is Pathogenic according to our data. Variant chr17-50191805-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 811940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50191805-C-T is described in Lovd as [Pathogenic]. Variant chr17-50191805-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.2110G>A	p.Gly704Ser	missense_variant	31/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.1912G>A	p.Gly638Ser	missense_variant	28/48
COL1A1	XM_005257058.5	c.2110G>A	p.Gly704Ser	missense_variant	31/49
COL1A1	XM_005257059.5	c.1192G>A	p.Gly398Ser	missense_variant	18/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.2110G>A	p.Gly704Ser	missense_variant	31/51	1	NM_000088.4	P1
COL1A1	ENST00000476387.1	n.459G>A		non_coding_transcript_exon_variant	7/9	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438716 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 713516

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta, perinatal lethal Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	Jul 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jan 30, 2022	The heterozygous mis-sense insertion variant c.2110G>A (p.G704S) has been previously reported by Normand E A et al in 2018 and it has not been observed in gnomAD and 1000g. In-silico bioinformatic software predict this variant by mutation taster as Disease causing and SIFT & PROVEAN as Damaging. The phenotype observed was micromelia, rhizomelia, mesomelia, short and bowed long bones, poorly ossified skull bones and clubfoot. Osteogenesis Imperfecta type II is an autosomal dominant disorder. Based on the phenotypic observation, we classify this variant as pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 19, 2019

The COL1A1 c.2110G>A; p.Gly704Ser variant (rs67368147), also reported as Gly526Ser, has been described in individuals affected with osteogenesis imperfecta (OI; see link to OI database and references therein, Ward 2001). It is absent from general population databases (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). Additionally, another amino acid change at this position (c.2110G>T; p.Gly704Cys) has been reported in association with OI and is considered pathogenic (Starman 1989). Based on available information, the p.Gly704Ser variant is considered pathogenic. REFERENCES Link to OI variant database: https://oi.gene.le.ac.uk/home.php?select_db=COL1A1 Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Starman B et al. Osteogenesis imperfecta. The position of substitution for glycine by cysteine in the triple helical domain of the pro alpha 1(I) chains of type I collagen determines the clinical phenotype. J Clin Invest. 1989 Oct;84(4):1206-14. Ward L et al. Thirty-three novel COL1A1 and COL1A2 mutations in patients with osteogenesis imperfecta types I-IV. Hum Mutat. 2001 May;17(5):434. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 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.; Not observed 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: 11317364, 21239989, 17078022, 30266093) -

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 29, 2021

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). 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. This variant has been observed in individual(s) with clinical features of osteogenesis imperfecta (PMID: 11317364, 30266093, 17078022). This variant is also known as G526S. ClinVar contains an entry for this variant (Variation ID: 811940). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 704 of the COL1A1 protein (p.Gly704Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	1.0
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.041	D
Vest4		0.99
MutPred		0.99		Gain of glycosylation at G704 (P = 0.0074);
MVP		0.99
MPC		1.5
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: rs67368147; hg19: chr17-48269166;