17-50189419-GCCAGGGGGA-GCCAGGGGGACCAGGGGGA

Variant names:

• chr17-50189419-G-GCCAGGGGGA
• rs1555572458
• NM_000088.4:c.2778_2786dupTCCCCCTGG

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_000088.4(COL1A1):​c.2778_2786dupTCCCCCTGG​(p.Gly929_Pro930insProProGly) variant causes a disruptive 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.87
• Publications: 0 publications found

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]

COL1A1 Gene-Disease associations (from GenCC):

• Caffey disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, arthrochalasia type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ehlers-Danlos/osteogenesis imperfecta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• high bone mass osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 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 17-50189419-G-GCCAGGGGGA is Pathogenic according to our data. Variant chr17-50189419-G-GCCAGGGGGA is described in ClinVar as [Pathogenic]. Clinvar id is 456756.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.2778_2786dupTCCCCCTGG	p.Gly929_Pro930insProProGly	disruptive_inframe_insertion	Exon 39 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.2580_2588dupTCCCCCTGG	p.Gly863_Pro864insProProGly	disruptive_inframe_insertion	Exon 36 of 48		XP_011522643.1
COL1A1	XM_005257059.5	c.1860_1868dupTCCCCCTGG	p.Gly623_Pro624insProProGly	disruptive_inframe_insertion	Exon 26 of 38		XP_005257116.2
COL1A1	XM_005257058.5	c.2667+251_2667+259dupTCCCCCTGG		intron_variant	Intron 38 of 48		XP_005257115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.2778_2786dupTCCCCCTGG	p.Gly929_Pro930insProProGly	disruptive_inframe_insertion	Exon 39 of 51	1	NM_000088.4	ENSP00000225964.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:1

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with clinical features of osteogenesis imperfecta (Invitae). 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.2778_2786dup, results in the insertion of 3 amino acid(s) of the COL1A1 protein (p.Pro928_Pro930dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

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

Other links and lift over

dbSNP: rs1555572458; hg19: chr17-48266780;