NM_022356.4(P3H1):c.2176_2177del (p.Ser726fs) AND Osteogenesis imperfecta type 8

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 26, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003601804.2

Allele description [Variation Report for NM_022356.4(P3H1):c.2176_2177del (p.Ser726fs)]

NM_022356.4(P3H1):c.2176_2177del (p.Ser726fs)

Gene:

P3H1:prolyl 3-hydroxylase 1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

1p34.2

Genomic location:

Preferred name:

NM_022356.4(P3H1):c.2176_2177del (p.Ser726fs)

HGVS:

NC_000001.11:g.42746731GA[3]
NG_008123.1:g.25347TC[3]
NM_001146289.2:c.*95TC[3]
NM_001243246.2:c.*174TC[3]
NM_022356.4:c.2176_2177delMANE SELECT
NP_071751.3:p.Ser726Argfs
NP_071751.3:p.Ser726fs
LRG_5t1:c.2170_2171TC[3]
LRG_5t2:c.*95_*96TC[3]
LRG_5t3:c.*174_*175TC[3]
LRG_5:g.25347TC[3]
LRG_5p1:p.Ser726Argfs
NC_000001.10:g.43212402GA[3]
NC_000001.10:g.43212402_43212403del
NM_001146289.1:c.*95_*96TC[3]
NM_001243246.1:c.*174_*175TC[3]
NM_022356.2:c.*174_*175TC[3]
NM_022356.3:c.2170_2171TC[3]

Protein change:

S726fs

Molecular consequence:

NM_001146289.2:c.*95TC[3] - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001243246.2:c.*174TC[3] - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_022356.4:c.2176_2177del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Osteogenesis imperfecta type 8 (OI8)
Synonyms:: OI type VIII
Identifiers:: MONDO: MONDO:0012581; MedGen: C1970458; OMIM: 610915

Recent activity

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C22orf1 [Homo sapiens]
C22orf1 [Homo sapiens]
gi|90403032|emb|CAJ86442.1|

Protein
regulation of nuclear pre-mRNA domain-containing protein 1A isoform 1 [Homo sapi...
regulation of nuclear pre-mRNA domain-containing protein 1A isoform 1 [Homo sapiens]
gi|21361709|ref|NP_060640.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004427424	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 26, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 3545499, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004427424

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 26, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A C-terminal signal prevents secretion of luminal ER proteins.

Munro S, Pelham HR.

Cell. 1987 Mar 13;48(5):899-907.

PubMed [citation]

PMID:: 3545499

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004427424.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Ser726Argfs*3) in the P3H1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the P3H1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with P3H1-related conditions. This variant disrupts the KDEL domain (p.Lys733-p.Leu736) of the P3H1 protein that is required for the cellular retention and activity of certain types of proteins (PMID: 3545499). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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