rs74315111

Variant names:

• chr17-50188578-GGCACCAGGA-G
• rs74315111
• NM_000088.4:c.3150_3158delTCCTGGTGC

Your query was ambiguous. Multiple possible variants found:

• chr17-50188578-GGCACCAGGA-G
• chr17-50188578-GGCACCAGGA-GGCACCAGGAGCACCAGGA

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4 PP3 PP5_Very_Strong

The NM_000088.4(COL1A1):​c.3150_3158delTCCTGGTGC​(p.Pro1051_Ala1053del) variant causes a disruptive 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 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• 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 13 ACMG points.

• 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 rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.3150_3158delTCCTGGTGC	p.Pro1051_Ala1053del	disruptive_inframe_deletion	Exon 43 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.2952_2960delTCCTGGTGC	p.Pro985_Ala987del	disruptive_inframe_deletion	Exon 40 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.2880_2888delTCCTGGTGC	p.Pro961_Ala963del	disruptive_inframe_deletion	Exon 41 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.2232_2240delTCCTGGTGC	p.Pro745_Ala747del	disruptive_inframe_deletion	Exon 30 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.3150_3158delTCCTGGTGC	p.Pro1051_Ala1053del	disruptive_inframe_deletion	Exon 43 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000511732.1	n.94_102delTCCTGGTGC		non_coding_transcript_exon_variant	Exon 2 of 2	2
COL1A1	ENST00000486572.1	n.-33_-25delTCCTGGTGC		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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta, perinatal lethal Pathogenic:3

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Dec 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jun 29, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis imperfecta type I Pathogenic:2

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). 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 also known as deletion of 9 base pairs, 868-876, single Gly-Ala-Pro triplet. ClinVar contains an entry for this variant (Variation ID: 372753). 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). For these reasons, this variant has been classified as Pathogenic. -

Osteogenesis imperfecta Pathogenic:1

Jun 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COL1A1-related disorder Pathogenic:1

Dec 22, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 10, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;