rs72648326
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
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). Synonymous variant affecting the same amino acid position (i.e. R415R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000088.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.1243C>T | p.Arg415Ter | stop_gained | 19/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.1045C>T | p.Arg349Ter | stop_gained | 16/48 | ||
COL1A1 | XM_005257058.5 | c.1243C>T | p.Arg415Ter | stop_gained | 19/49 | ||
COL1A1 | XM_005257059.5 | c.957+1026C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.1243C>T | p.Arg415Ter | stop_gained | 19/51 | 1 | NM_000088.4 | 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: 1AN: 1461624Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727114
GnomAD4 genome Cov.: 32
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at