rs1555572458

Positions:

• chr17-50189419-GCCAGGGGGA-G
• chr17-50189419-GCCAGGGGGA-GCCAGGGGGACCAGGGGGA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM4 PP3 PP5_Moderate

The NM_000088.4(COL1A1):​c.2778_2786del​(p.Pro928_Pro930del) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 7 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 17-50189419-GCCAGGGGGA-G is Pathogenic according to our data. Variant chr17-50189419-GCCAGGGGGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 811486.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.2778_2786del	p.Pro928_Pro930del	inframe_deletion	39/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_005257059.5	c.1860_1868del	p.Pro622_Pro624del	inframe_deletion	26/38		XP_005257116.2
COL1A1	XM_011524341.2	c.2580_2588del	p.Pro862_Pro864del	inframe_deletion	36/48		XP_011522643.1
COL1A1	XM_005257058.5	c.2667+251_2667+259del		intron_variant			XP_005257115.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.2778_2786del	p.Pro928_Pro930del	inframe_deletion	39/51	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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 24, 2019

The COL1A1 c.2778_2786delTCCCCCTGG; p.Pro928_Pro930del variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes three amino acid residues leaving the rest of the protein in-frame, but occurs in the critical triple helical domain (Ben Amor 2011). Other short in-frame deletions and duplications in this region of the protein have been reported in individuals with osteogenesis imperfecta and are considered pathogenic (Hawkins 1991, Pace 2001, Ries-Levavi 2004). Based on available information, the p.Pro928_Pro930del variant is considered to be likely pathogenic. References: Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. Hawkins JR et al. A 9-base pair deletion in COL1A1 in a lethal variant of osteogenesis imperfecta. J Biol Chem. 1991 Nov 25;266(33):22370-4. Pace JM et al. Deletions and duplications of Gly-Xaa-Yaa triplet repeats in the triple helical domains of type I collagen chains disrupt helix formation and result in several types of osteogenesis imperfecta. Hum Mutat. 2001 Oct;18(4):319-26. Ries-Levavi L et al. Genetic and biochemical analyses of Israeli osteogenesis imperfecta patients. Hum Mutat. 2004 Apr;23(4):399-400. -

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: rs1555572458; hg19: chr17-48266780;