rs1135401953

Positions:

• chr17-50195284-C-A
• chr17-50195284-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.1247G>T​(p.Gly416Val) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G416D) 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:2
• Conservation: PhyloP100: 7.91

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 4 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 chr17-50195284-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 431382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, COL1A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 17-50195284-C-A is Pathogenic according to our data. Variant chr17-50195284-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 993947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.1247G>T	p.Gly416Val	missense_variant	19/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.1049G>T	p.Gly350Val	missense_variant	16/48
COL1A1	XM_005257058.5	c.1247G>T	p.Gly416Val	missense_variant	19/49
COL1A1	XM_005257059.5	c.957+1030G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.1247G>T	p.Gly416Val	missense_variant	19/51	1	NM_000088.4	P1
COL1A1	ENST00000471344.1	n.191G>T		non_coding_transcript_exon_variant	3/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Genetics Department, Polish Mother's Memorial Hospital Research Institute

Feb 16, 2023

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 10, 2019

The COL1A1 c.1247G>T; p.Gly416Val variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 416 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. 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). Additionally, several other surrounding glycine substitutions in this exon have been reported in individuals affected with osteogenesis imperfect types II and IV and are considered pathogenic (Marini 2007). Based on available information, this variant is considered to be likely pathogenic. References: Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Marini J 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.95
MutPred		0.99		Loss of methylation at R415 (P = 0.0647);
MVP		0.99
MPC		0.70
ClinPred		1.0	D
GERP RS		5.6
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: rs1135401953; hg19: chr17-48272645;