chr17-50198169-CA-C

Variant names:

• chr17-50198169-CA-C
• rs72667023
• NM_000088.4:c.579delT

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.579delT​(p.Gly194ValfsTer71) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL1A1 NM_000088.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.0310

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 17-50198169-CA-C is Pathogenic according to our data. Variant chr17-50198169-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50198169-CA-C is described in Lovd as [Pathogenic]. Variant chr17-50198169-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.579delT	p.Gly194ValfsTer71	frameshift_variant	Exon 7 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.579delT	p.Gly194ValfsTer71	frameshift_variant	Exon 7 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.579delT	p.Gly194ValfsTer71	frameshift_variant	Exon 7 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.579delT	p.Gly194ValfsTer71	frameshift_variant	Exon 7 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.579delT	p.Gly194ValfsTer71	frameshift_variant	Exon 7 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000495677.1	n.306delT		non_coding_transcript_exon_variant	Exon 2 of 8	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jun 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36709916, 37334733, 35909573, 34902613, 36951356, 25944380, 19358256, 22679784, 23195995, 27510842, 26627451, 16879195, 21884818, 32034735, 28528406, 29502568, 32166892, 21667357) -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL1A1: PVS1, PM2, PS4:Moderate -

Osteogenesis imperfecta type I Pathogenic:3

Mar 07, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000035925 /PMID: 16879195). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

-

Department of Medical Sciences, Uppsala University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly194Valfs*71) 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 individual(s) with osteogenesis imperfecta (PMID: 16879195, 27510842). ClinVar contains an entry for this variant (Variation ID: 35925). For these reasons, this variant has been classified as Pathogenic. -

Osteogenesis imperfecta Pathogenic:2

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Postmenopausal osteoporosis Pathogenic:1

Jun 14, 2021

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs72667023; hg19: chr17-48275530;