rs72645369

chr17-50195594-AG-Achr17-50195594-AG-AGG

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.1127del(p.Pro376LeufsTer165) 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:4
• Conservation: PhyloP100: 6.77

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 17-50195594-AG-A is Pathogenic according to our data. Variant chr17-50195594-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 859292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50195594-AG-A is described in Lovd as [Pathogenic]. Variant chr17-50195594-AG-A is described in Lovd as [Pathogenic]. Variant chr17-50195594-AG-A is described in Lovd as [Pathogenic]. Variant chr17-50195594-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.1127del	p.Pro376LeufsTer165	frameshift_variant	17/51	ENST00000225964.10
COL1A1	XM_005257058.5	c.1127del	p.Pro376LeufsTer165	frameshift_variant	17/49
COL1A1	XM_005257059.5	c.957+719del		intron_variant
COL1A1	XM_011524341.2	c.958-117del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.1127del	p.Pro376LeufsTer165	frameshift_variant	17/51	1	NM_000088.4	P1
COL1A1	ENST00000471344.1	n.71del		non_coding_transcript_exon_variant	1/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Feb 26, 2021	The variant c.1127delC (p.Pro376Leufs * 165) in the COL1A1 gene is reported as a pathogenic for osteogenesis imperfecta I in ClinVar (Variation ID: 859292). This variant creates a shift in the reading frame which is predicted to result in a premature stop codon 165 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). There is no frequency information in the gnomAD or 1000 Genomes Project databases. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 11, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Pro376Leufs*165) in the COL1A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with osteogenesis imperfecta type I (PMID: 8808594). ClinVar contains an entry for this variant (Variation ID: 859292). -

Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Apr 01, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 8808594, 23729740) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs72645369; hg19: chr17-48272955;