rs72651634

Positions:

• chr17-50191997-CA-C

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.2010del​(p.Gly671AlafsTer95) 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 (★★). 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:5
• Conservation: PhyloP100: -0.490

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 17-50191997-CA-C is Pathogenic according to our data. Variant chr17-50191997-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 497350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50191997-CA-C is described in Lovd as [Pathogenic]. Variant chr17-50191997-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.2010del	p.Gly671AlafsTer95	frameshift_variant	30/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.1812del	p.Gly605AlafsTer95	frameshift_variant	27/48		XP_011522643.1
COL1A1	XM_005257058.5	c.2010del	p.Gly671AlafsTer95	frameshift_variant	30/49		XP_005257115.2
COL1A1	XM_005257059.5	c.1092del	p.Gly365AlafsTer95	frameshift_variant	17/38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.2010del	p.Gly671AlafsTer95	frameshift_variant	30/51	1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000476387.1	n.359del		non_coding_transcript_exon_variant	6/9	2
COL1A1	ENST00000504289.1	n.442del		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 30, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 22, 2022	PM2_supporting, PS4_moderate, PVS1 -

COL1A1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2024

The COL1A1 c.2010delT variant is predicted to result in a frameshift and premature protein termination (p.Gly671Alafs*95). This variant has been reported to be causative for osteogenesis imperfecta (OI) (Table 1, Family Hu7, Reported as P492fsX587, Ward et al. 2001. PubMed ID: 11317364; Patient 3, Balasubramanian et al. 2016. PubMed ID: 26863094; Supplementary Table 2, Bertoli-Avella et al. 2020. PubMed ID: 32860008; Table 3, Patient ID 31, Higuchi et al. 2021. PubMed ID: 33939306). This variant was also reported, along with a COL5A1 variant, in a family with a compound phenotype of OI and Ehlers-Danlos syndrome (Lin et al. 2019. PubMed ID: 31239369). Of note, two family members had both variants and the compound phenotypes, while two other members only had the COL1A1 variant and only the OI phenotype. This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Osteogenesis imperfecta, perinatal lethal Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

-

- -

Osteogenesis imperfecta type I Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 16, 2023

ClinVar contains an entry for this variant (Variation ID: 497350). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with osteogenesis imperfecta type I (PMID: 11317364; Invitae). This sequence change creates a premature translational stop signal (p.Gly671Alafs*95) 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72651634; hg19: chr17-48269358;