rs72648326

Positions:

• chr17-50195288-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000088.4(COL1A1):​c.1243C>T​(p.Arg415Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,624 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 Conflicting classifications of pathogenicity (no stars). 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 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 8.13

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 11 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 17-50195288-G-A is Pathogenic according to our data. Variant chr17-50195288-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 425597.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=8}. Variant chr17-50195288-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-50195288-G-A is described in Lovd as [Pathogenic]. Variant chr17-50195288-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1243C>T	p.Arg415Ter	stop_gained	19/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.1045C>T	p.Arg349Ter	stop_gained	16/48		XP_011522643.1
COL1A1	XM_005257058.5	c.1243C>T	p.Arg415Ter	stop_gained	19/49		XP_005257115.2
COL1A1	XM_005257059.5	c.957+1026C>T		intron_variant			XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1243C>T	p.Arg415Ter	stop_gained	19/51	1	NM_000088.4	ENSP00000225964	P1
COL1A1	ENST00000471344.1	n.187C>T		non_coding_transcript_exon_variant	3/8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461624 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2024	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: 36709916, 37270749, 31447884, 27132807, 15741671, 8613526, 22679784, 8808594, 27748872, 31414283, 31363794, 15024745, 25944380, 31794058, 32166892, 33939306, 35909573, 35822426, 35186396, 37334733, 27535533) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 02, 2022	- -

Osteogenesis imperfecta type I Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Arg415*) 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 1 (PMID: 8613526, 8808594, 15024745, 25944380, 27132807). ClinVar contains an entry for this variant (Variation ID: 425597). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Medical Sciences, Uppsala University	-	- -

Infantile cortical hyperostosis;C0023931:Osteogenesis imperfecta type I;C0029456:Osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4551623:Ehlers-Danlos syndrome, arthrochalasia type;C5436842:Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

COL1A1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2024

The COL1A1 c.1243C>T variant is predicted to result in premature protein termination (p.Arg415*). This variant was reported in multiple individuals with osteogenesis imperfecta (see example: Higuchi et al. 2021. PubMed ID: 33939306; Hruskova et al. 2016. PubMed ID: 27132807; Morlino et al. 2020. PubMed ID: 31794058). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in COL1A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

-

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is 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: VCV000425597 / PMID: 8808594). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Infantile cortical hyperostosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Osteogenesis imperfecta, perinatal lethal Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Jun 02, 2023

The observed missense c.496G>A (p.Val166Ile) variant in POLR3A gene has been previously reported in compound heterozygous state in individuals affected with Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism (Wolf NI et al. 2014). The p.Val166Ile variant has allele frequency 0.005% gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen -Probably damaging, SIFT - Tolerated and Mutation Taster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid on POLR3A gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant has been reported to the ClinVar database as Uncertain_significance with a status of criteria provided, single submitter. The amino acid change p.Val166Ile in POLR3A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A
Vest4		0.89
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72648326; hg19: chr17-48272649;