rs1555574802

chr17-50198184-GAC-GT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000088.4(COL1A1):c.563_564delinsA(p.Gly188AspfsTer77) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL1A1 NM_000088.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.17

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50198185-AC-T is Pathogenic according to our data. Variant chr17-50198185-AC-T is described in ClinVar as [Pathogenic]. Clinvar id is 456791.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.563_564delinsA	p.Gly188AspfsTer77	frameshift_variant	7/51	ENST00000225964.10
COL1A1	XM_005257058.5	c.563_564delinsA	p.Gly188AspfsTer77	frameshift_variant	7/49
COL1A1	XM_005257059.5	c.563_564delinsA	p.Gly188AspfsTer77	frameshift_variant	7/38
COL1A1	XM_011524341.2	c.563_564delinsA	p.Gly188AspfsTer77	frameshift_variant	7/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.563_564delinsA	p.Gly188AspfsTer77	frameshift_variant	7/51	1	NM_000088.4	P1
COL1A1	ENST00000495677.1	n.290_291delinsA		non_coding_transcript_exon_variant	2/8	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 09, 2020

PVS1, PM2, PP4 -

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 16, 2016

This sequence change deletes 2 nucleotide and inserts 1 nucleotides in exon 7 of the COL1A1 mRNA (c.563_564delinsA), causing a frameshift at codon 188. This creates a premature translational stop signal (p.Gly188Aspfs*77) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in COL1A1 are known to be pathogenic (PMID: 15864348, 9295084, 2794057). For these reasons, this variant has been classified as Pathogenic. -

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: rs1555574802; hg19: chr17-48275546;