17-50188578-GGCACCAGGA-GGCACCAGGAGCACCAGGA

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000088.4(COL1A1):c.3158_3159insTCCTGGTGC(p.Ala1053_Gly1055dup) variant causes a inframe insertion 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.99

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 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000088.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000088.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 17-50188578-G-GGCACCAGGA is Pathogenic according to our data. Variant chr17-50188578-G-GGCACCAGGA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372752.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.3158_3159insTCCTGGTGC	p.Ala1053_Gly1055dup	inframe_insertion	43/51	ENST00000225964.10
COL1A1	XM_005257058.5	c.2888_2889insTCCTGGTGC	p.Ala963_Gly965dup	inframe_insertion	41/49
COL1A1	XM_005257059.5	c.2240_2241insTCCTGGTGC	p.Ala747_Gly749dup	inframe_insertion	30/38
COL1A1	XM_011524341.2	c.2960_2961insTCCTGGTGC	p.Ala987_Gly989dup	inframe_insertion	40/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.3158_3159insTCCTGGTGC	p.Ala1053_Gly1055dup	inframe_insertion	43/51	1	NM_000088.4	P1
COL1A1	ENST00000511732.1	n.102_103insTCCTGGTGC		non_coding_transcript_exon_variant	2/2	2
COL1A1	ENST00000486572.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 07, 2019

- -

COL1A1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2024

The COL1A1 c.3150_3158dup9 variant is predicted to result in an in-frame duplication (p.Ala1053_Gly1055dup). This variant has been reported to be causative for osteogenesis imperfecta (OI) due to disrupted helix formation (reported as c.3150_3158dup, p.Pro1051_Ala1053dup at Pyott et al. 2011. PubMed ID: 21239989; reported as 3145_3153dupGGTGCTCCT at Pace et al. 2001. PubMed ID: 11668615). At PreventionGenetics, this variant has been reported in a fetus with severe intrauterine growth restriction, short long bones and ribs, bell-shaped thorax, short ribs, strawberry shated calvarial, and tibial and fibular bowing. 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 09, 2022

In-frame insertion of 3 amino acids within the triple-helical region and is predicted to add one canonical Gly-X-Y repeat unit to critically alter the protein. Variants affecting these repeats disrupt normal protein folding and function, and this is an established mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12538651, 21239989, 11668615, 18996919) -

Osteogenesis imperfecta, perinatal lethal Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 21, 2003

- -

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

This variant has been observed in individual(s) with clinical features of osteogenesis imperfecta (PMID: 11668615, 12538651; Invitae). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372752). This variant is also known as 3145_3153dupGGTGCTCCT (GAO871_873dup). This variant is not present in population databases (gnomAD no frequency). This variant, c.3150_3158dup, results in the insertion of 3 amino acid(s) of the COL1A1 protein (p.Ala1053_Gly1055dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74315111; hg19: chr17-48265939;