VCV000001253.45 - ClinVar

NM_022356.4(P3H1):c.1080+1G>T

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022356.4(P3H1):c.1080+1G>T

Variation ID: 1253 Accession: VCV000001253.45

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.2 1: 42757782 (GRCh38) [ NCBI UCSC ] 1: 43223453 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 3, 2016	Oct 20, 2024	Jan 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_022356.4:c.1080+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001146289.2:c.1080+1G>T		splice donor
NM_001243246.2:c.1080+1G>T		splice donor
NC_000001.11:g.42757782C>A
NC_000001.10:g.43223453C>A
NG_008123.1:g.14303G>T
LRG_5:g.14303G>T
LRG_5t1:c.1080+1G>T

... more HGVS ... less HGVS

Protein change

Other names

P3H1, IVS5, G-T, +1
IVS5, G-T, +1

Canonical SPDI

NC_000001.11:42757781:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00060 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00021

Exome Aggregation Consortium (ExAC) 0.00022

1000 Genomes Project 30x 0.00047

1000 Genomes Project 0.00060

Trans-Omics for Precision Medicine (TOPMed) 0.00066

The Genome Aggregation Database (gnomAD) 0.00068

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00100

Links

ClinGen: CA212756 OMIM: 610339.0001 dbSNP: rs72659351 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 17277775 Fig. S1 to determine the location of this allele on the current reference sequence.

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
P3H1		-	-	GRCh38 GRCh37	847	883

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Osteogenesis imperfecta type 8	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jan 5, 2024	RCV000001315.29
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 1, 2022	RCV000255762.22
Osteogenesis imperfecta	Pathogenic (1)	criteria provided, single submitter	Oct 1, 2018	RCV002276526.4
P3H1-related disorder	Pathogenic (1)	no assertion criteria provided	Jan 18, 2024	RCV003914795.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 22, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331786.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=P3H1 Number of individuals with the variant: 5 Sex: mixed
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta type 8 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893351.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Mar 12, 2020)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Osteogenesis imperfecta type 8 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159967.2 First in ClinVar: Feb 09, 2020 Last updated: Jan 26, 2021	Comment: The P3H1 c.1080+1G>T variant (rs72659351) is a West African founder mutation that has been described in the homozygous and compound heterozygous states in multiple individuals … (more) The P3H1 c.1080+1G>T variant (rs72659351) is a West African founder mutation that has been described in the homozygous and compound heterozygous states in multiple individuals affected with osteogenesis imperfecta (Cabral 2007, Cabral 2012, Fratzl-Zelman 2016). It is reported as pathogenic in ClinVar (Variation ID: 1253) and observed in the African population at an overall frequency of 0.25% (59/24040 alleles) in the Genome Aggregation Database. This variant abolishes the canonical splice donor site of intron 5, and analysis of fibroblasts from affected patients carrying this variant demonstrated decreased transcript, absent P3H1 protein expression, and impaired collagen secretion (Cabral 2007). Based on available information, this variant is considered pathogenic. REFERENCES Cabral WA et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet. 2007 Mar;39(3):359-65. Cabral WA et al. A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. Genet Med. 2012 May;14(5):543-51. Fratzl-Zelman N et al. Non-Lethal Type VIII Osteogenesis Imperfecta Has Elevated Bone Matrix Mineralization. J Clin Endocrinol Metab. 2016 Sep;101(9):3516-25. (less)
Pathogenic (Oct 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002564941.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022
Pathogenic (Nov 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002821024.14 First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024	Comment: P3H1: PVS1, PM2, PM3 Number of individuals with the variant: 1
Pathogenic (Apr 12, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000322319.9 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: Common founder splice variant in individuals of West African ancestry (Cabral et al., 2012); Canonical splice site variant in a gene for which loss-of-function is … (more) Common founder splice variant in individuals of West African ancestry (Cabral et al., 2012); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24498616, 27644073, 27509835, 29150909, 25525159, 17277775, 27383115, 26634552, 26525746, 30246063, 31085342, 31429852, 31589614, 32123938, 22281939) (less)
Pathogenic (Apr 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta type 8 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003806878.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 strong, PP1 strong Number of individuals with the variant: 1 Clinical Features: Fetal growth restriction (present) , Decreased body weight (present) , Bowing of limbs due to multiple fractures (present) , Bowed humerus (present) , Neonatal respiratory … (more) Fetal growth restriction (present) , Decreased body weight (present) , Bowing of limbs due to multiple fractures (present) , Bowed humerus (present) , Neonatal respiratory distress (present) , Femoral bowing (present) , Pseudoarthrosis (present) , Bowed forearm bones (present) , Severe intrauterine growth retardation (present) , Short stature (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Mar 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta type 8 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV003932203.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Comment: PVS1, PS3, PM3_Strong
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteogenesis imperfecta type 8 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004172078.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023
Pathogenic (Jan 05, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Osteogenesis imperfecta type 8 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000821229.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (8) PubMed: 28492532‚ 16199547‚ 17277775‚ 18566967‚ 19088120‚ 22281939‚ 27509835‚ 29150909 Comment: This sequence change affects a donor splice site in intron 5 of the P3H1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects a donor splice site in intron 5 of the P3H1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in P3H1 are known to be pathogenic (PMID: 17277775, 18566967, 19088120, 22281939). This variant is present in population databases (rs72659351, gnomAD 0.2%). Disruption of this splice site has been observed in individual(s) with osteogenesis imperfecta (PMID: 17277775, 22281939, 27509835, 29150909). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1253). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 01, 2012)	no assertion criteria provided Method: literature only	OSTEOGENESIS IMPERFECTA, TYPE VIII Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021465.3 First in ClinVar: Apr 04, 2013 Last updated: Jul 03, 2016	Publications: PubMed (2) PubMed: 17277775‚ 22281939 Comment on evidence: In 2 probands with osteogenesis imperfecta type VIII (610915), Cabral et al. (2007) found homozygosity for a splice site mutation of the LEPRE1 gene: IVS5+1G-T. … (more) In 2 probands with osteogenesis imperfecta type VIII (610915), Cabral et al. (2007) found homozygosity for a splice site mutation of the LEPRE1 gene: IVS5+1G-T. The first proband was born of nonconsanguineous Ghanaian parents; the second, of African American parents. The same mutation was present in compound heterozygous state with IVS9+1G-T (610339.0002) in 1 case and with a single-nucleotide deletion (610339.0003) in another. Cabral et al. (2007) postulated that this mutant allele originated and persisted in West African populations and was transported to North America. To determined the carrier frequency of the LEPRE1 (1080+1G-T) mutation, Cabral et al. (2012) screened genomic DNA African American and African cohorts. Among 3,055 African Americans from the Mid-Atlantic United States tested, 12 carriers were identified for a frequency of 0.39% (1 in 255). Among Ghanaians, 9 carriers were found among 453 individuals for a frequency of 1.99% (1 in 50). Among Nigerians, 10 of 818 were carriers (1.22%, 1 in 182). Among total West Africans, 19 of 1,284 were carriers (1.48%, 1 in 68). The mutation was not detected in Africa outside of West Africa. Among 12 unrelated West African families with 16 independent mutant alleles, Cabral et al. (2012) identified a conserved haplotype surrounding the LEPRE1 gene extending from between D1S2861 to the region between markers STR3 and STR5. Using linkage disequilibrium analysis, Cabral et al. (2012) estimated the mutation to have originated 650 and 900 years before the present (1100 to 1350 CE). (less)
Pathogenic (Jan 18, 2024)	no assertion criteria provided Method: clinical testing	P3H1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004732219.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The P3H1 c.1080+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is also referred to as IVS5+1G>T … (more) The P3H1 c.1080+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is also referred to as IVS5+1G>T in the literature. It is a founder variant in individuals of West African descent and has been reported in the homozygous and compound heterozygous state in multiple individuals with autosomal recessive osteogenesis imperfecta (Cabral et al. 2007. PubMed ID: 17277775; Cabral et al. 2012. PubMed ID: 22281939; Fratzl-Zelman et al. 2016. PubMed ID: 27383115; Bardai et al. 2016. PubMed ID: 27509835; Santana et al. 2018. PubMed ID: 30246063; Trancozo et al. 2019. PubMed ID: 31429852). This variant is reported in 0.25% of alleles in individuals of African descent in gnomAD, which is consistent with this being a founder variant. Variants that disrupt the consensus splice donor site in P3H1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Comment:

The P3H1 c.1080+1G>T variant (rs72659351) is a West African founder mutation that has been described in the homozygous and compound heterozygous states in multiple individuals affected with osteogenesis imperfecta (Cabral 2007, Cabral 2012, Fratzl-Zelman 2016). It is reported as pathogenic in ClinVar (Variation ID: 1253) and observed in the African population at an overall frequency of 0.25% (59/24040 alleles) in the Genome Aggregation Database. This variant abolishes the canonical splice donor site of intron 5, and analysis of fibroblasts from affected patients carrying this variant demonstrated decreased transcript, absent P3H1 protein expression, and impaired collagen secretion (Cabral 2007). Based on available information, this variant is considered pathogenic. REFERENCES Cabral WA et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet. 2007 Mar;39(3):359-65. Cabral WA et al. A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. Genet Med. 2012 May;14(5):543-51. Fratzl-Zelman N et al. Non-Lethal Type VIII Osteogenesis Imperfecta Has Elevated Bone Matrix Mineralization. J Clin Endocrinol Metab. 2016 Sep;101(9):3516-25.

Comment:

Common founder splice variant in individuals of West African ancestry (Cabral et al., 2012); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24498616, 27644073, 27509835, 29150909, 25525159, 17277775, 27383115, 26634552, 26525746, 30246063, 31085342, 31429852, 31589614, 32123938, 22281939)

Comment:

This sequence change affects a donor splice site in intron 5 of the P3H1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in P3H1 are known to be pathogenic (PMID: 17277775, 18566967, 19088120, 22281939). This variant is present in population databases (rs72659351, gnomAD 0.2%). Disruption of this splice site has been observed in individual(s) with osteogenesis imperfecta (PMID: 17277775, 22281939, 27509835, 29150909). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1253). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The P3H1 c.1080+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is also referred to as IVS5+1G>T in the literature. It is a founder variant in individuals of West African descent and has been reported in the homozygous and compound heterozygous state in multiple individuals with autosomal recessive osteogenesis imperfecta (Cabral et al. 2007. PubMed ID: 17277775; Cabral et al. 2012. PubMed ID: 22281939; Fratzl-Zelman et al. 2016. PubMed ID: 27383115; Bardai et al. 2016. PubMed ID: 27509835; Santana et al. 2018. PubMed ID: 30246063; Trancozo et al. 2019. PubMed ID: 31429852). This variant is reported in 0.25% of alleles in individuals of African descent in gnomAD, which is consistent with this being a founder variant. Variants that disrupt the consensus splice donor site in P3H1 are expected to be pathogenic. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic analysis of osteogenesis imperfecta in the Palestinian population: molecular screening of 49 affected families.	Essawi O	Molecular genetics & genomic medicine	2018	PMID: 29150909
DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum.	Bardai G	Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA	2016	PMID: 27509835
A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta.	Cabral WA	Genetics in medicine : official journal of the American College of Medical Genetics	2012	PMID: 22281939
Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation.	Willaert A	Journal of medical genetics	2009	PMID: 19088120
CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta.	Baldridge D	Human mutation	2008	PMID: 18566967
Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta.	Cabral WA	Nature genetics	2007	PMID: 17277775
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=P3H1	-	-	-	-

Text-mined citations for rs72659351 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_022356.4(P3H1):c.1080+1G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72659351 ...