rs1555572401

Positions:

• chr17-50189193-CCTCT-C
• chr17-50189193-CCTCT-CCT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000225964.10(COL1A1):​c.2908_2911del​(p.Arg970AlafsTer137) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R970R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 ENST00000225964.10 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.82

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50189193-CCTCT-C is Pathogenic according to our data. Variant chr17-50189193-CCTCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 456758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.2908_2911del	p.Arg970AlafsTer137	frameshift_variant	40/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_005257059.5	c.1990_1993del	p.Arg664AlafsTer137	frameshift_variant	27/38		XP_005257116.2
COL1A1	XM_011524341.2	c.2710_2713del	p.Arg904AlafsTer137	frameshift_variant	37/48		XP_011522643.1
COL1A1	XM_005257058.5	c.2668-187_2668-184del		intron_variant			XP_005257115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.2908_2911del	p.Arg970AlafsTer137	frameshift_variant	40/51	1	NM_000088.4	ENSP00000225964	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2017	For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 2794057). This sequence change deletes 4 nucleotide from exon 40 of the COL1A1 mRNA (c.2908_2911delAGAG), causing a frameshift at codon 970. This creates a premature translational stop signal (p.Arg970Alafs*137) and is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 27, 2020	The COL1A1 c.2908_2911del variant is classified as a PATHOGENIC variant (PVS1, PM2, PP4) The COL1A1 c.2908_2911del deletes 4 nucleotides from exon 40 of the COL1A1 mRNA causing a frameshift at codon 970. This creates a premature translational stop signal (p.Arg970Alafs*137) and is expected to result in an absent or disrupted protein product. This variant has been reported in a patient with Osteogenesis imperfecta (PMID: 30715774) and other loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 2794057) (PVS1). The variant has been reported in ClinVar as pathogenic by another diagnostic laboratory (Variation ID: VCV000456758), and HGMD as damaging for Osteogenesis imperfecta (CD194665). The variant has not been reported in dbSNP and is absent from population databases (PM2). -

Osteogenesis imperfecta type III Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. Similarly affected sibling shares the variant. The variant has been reported to be associated with COL1A1 related disorder (ClinVar ID: VCV000456758). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

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: rs1555572401; hg19: chr17-48266554;