dbSNP rs72667036: COL1A1:p.Arg220* (chr17-50197770-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000088.4(COL1A1):c.658C>T(p.Arg220*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 10.0

Variant links:

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]

COL1A1 links:

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ACMG classification

Classification made for transcript

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 17-50197770-G-A is Pathogenic according to our data. Variant chr17-50197770-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 425637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50197770-G-A is described in Lovd as [Pathogenic]. Variant chr17-50197770-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4 link	c.658C>T	p.Arg220*	stop_gained	Exon 9 of 51	ENST00000225964.10	NP_000079.2	P02452
COL1A1	XM_011524341.2 link	c.658C>T	p.Arg220*	stop_gained	Exon 9 of 48		XP_011522643.1
COL1A1	XM_005257058.5 link	c.658C>T	p.Arg220*	stop_gained	Exon 9 of 49		XP_005257115.2
COL1A1	XM_005257059.5 link	c.658C>T	p.Arg220*	stop_gained	Exon 9 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 link	c.658C>T	p.Arg220*	stop_gained	Exon 9 of 51	1	NM_000088.4	ENSP00000225964.6		P02452
COL1A1	ENST00000495677.1 link	n.385C>T		non_coding_transcript_exon_variant	Exon 4 of 8	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452636

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722642

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type I

Pathogenic:4

Jul 15, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Stop-gained (nonsense): 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: VCV000425637 /PMID: 9443882 /3billion dataset). 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

- -

Jan 27, 2025

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.Arg220*) 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 present in population databases (rs72667036, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with osteogenesis imperfecta type 1 (PMID: 9443882, 18311573, 21667357, 22206639, 26627451). ClinVar contains an entry for this variant (Variation ID: 425637). For these reasons, this variant has been classified as Pathogenic. -

Osteogenesis imperfecta

Pathogenic:1

Aug 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, arthrochalasia type, 2

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Pathogenic:1

May 02, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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: 26627451, 22753364, 30984112, 24501682, 31414283, 32581362, 25944380, 9443882, 21667357, 22206639, 18311573, 34107839, 31447884) -

Stickler syndrome type 2

Pathogenic:1

Oct 02, 2024

Autoinflammatory diseases unit, CHU de Montpellier

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.98

Vest4

0.90

GERP RS

4.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over