rs74315111

chr17-50188578-GGCACCAGGA-Gchr17-50188578-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.3150_3158del(p.Ala1053_Gly1055del) variant causes a inframe deletion 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.09

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 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-GGCACCAGGA-G is Pathogenic according to our data. Variant chr17-50188578-GGCACCAGGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 372753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50188578-GGCACCAGGA-G is described in Lovd as [Pathogenic]. Variant chr17-50188578-GGCACCAGGA-G is described in Lovd as [Pathogenic]. Variant chr17-50188578-GGCACCAGGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.3150_3158del	p.Ala1053_Gly1055del	inframe_deletion	43/51	ENST00000225964.10
COL1A1	XM_005257058.5	c.2880_2888del	p.Ala963_Gly965del	inframe_deletion	41/49
COL1A1	XM_005257059.5	c.2232_2240del	p.Ala747_Gly749del	inframe_deletion	30/38
COL1A1	XM_011524341.2	c.2952_2960del	p.Ala987_Gly989del	inframe_deletion	40/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.3150_3158del	p.Ala1053_Gly1055del	inframe_deletion	43/51	1	NM_000088.4	P1
COL1A1	ENST00000511732.1	n.94_102del		non_coding_transcript_exon_variant	2/2	2
COL1A1	ENST00000486572.1			upstream_gene_variant		3

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2022	In-frame deletion of 3 amino acids in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Occurs in the triple helical domain and is predicted to remove canonical Gly-X-Y repeat units; an in-frame deletion variant in this region is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 1939261, 22795119, 28261977, 34025714, 21239989, 32627857) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2018	- -

Osteogenesis imperfecta, perinatal lethal Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Nov 09, 2017	- -

Osteogenesis imperfecta type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 22, 2022	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). ClinVar contains an entry for this variant (Variation ID: 372753). This variant is also known as deletion of 9 base pairs, 868-876, single Gly-Ala-Pro triplet. This variant has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome and/or osteogenesis imperfecta (PMID: 1939261, 28261977). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.3150_3158del, results in the deletion of 3 amino acid(s) of the COL1A1 protein (p.Ala1053_Gly1055del), but otherwise preserves the integrity of the reading frame. -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -

Osteogenesis imperfecta Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2020

- -

COL1A1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2022

The COL1A1 c.3150_3158del9 variant is predicted to result in an in-frame deletion (p.Ala1053_Gly1055del). This variant was reported to have occurred de novo in multiple cases of lethal type osteogenesis imperfecta (Hawkins and Steinmann. 1991. PubMed ID: 1939261; Chen et al. 2012. PubMed ID: 22795119; Corsten-Janssen et al. 2020. PubMed ID: 32627857). In the mosaic state, this variant was documented in a milder manifestation (Symoens et al. 2017. PubMed ID: 28261977). Functional studies showed that this variant results in overmodification of the mutant type I collagen (Hawkins and Steinmann. 1991. PubMed ID: 1939261; Symoens et al. 2017. PubMed ID: 28261977). 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. -

Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 10, 2020

- -

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;