chr17-50185564-A-AGGGG

Position:

• chr17-50185564-A-AGGGG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000225964.10(COL1A1):​c.4332_4333insCCCC​(p.Leu1445ProfsTer107) variant causes a frameshift change involving the alteration of a non-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: 29)
• Consequence: COL1A1 ENST00000225964.10 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.31

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-50185564-A-AGGGG is Pathogenic according to our data. Variant chr17-50185564-A-AGGGG is described in ClinVar as [Pathogenic]. Clinvar id is 526845.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.4332_4333insCCCC	p.Leu1445ProfsTer107	frameshift_variant	51/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.4062_4063insCCCC	p.Leu1355ProfsTer107	frameshift_variant	49/49		XP_005257115.2
COL1A1	XM_005257059.5	c.3414_3415insCCCC	p.Leu1139ProfsTer107	frameshift_variant	38/38		XP_005257116.2
COL1A1	XM_011524341.2	c.4134_4135insCCCC	p.Leu1379ProfsTer107	frameshift_variant	48/48		XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.4332_4333insCCCC	p.Leu1445ProfsTer107	frameshift_variant	51/51	1	NM_000088.4	ENSP00000225964	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 25, 2018

This sequence change results in a frameshift in the COL1A1 gene (p.Leu1445Profs*107). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acids of the COL1A1 protein and extend the protein by an additional 87 amino acids. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with osteogenesis imperfecta (Invitae). ClinVar contains an entry for this variant (Variation ID: 526845). This variant results in an extension of the COL1A1 protein. Other variant(s) that result in a similarly extended protein product (p.Ala1443Glyfs*110 and p.Glu1453Arg*96) have been determined to be pathogenic (PMID: 2295701, Invitae). This suggests that these extensions are likely to be causative of disease. 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: rs1114167405; hg19: chr17-48262925;