NM_004329.3(BMPR1A):c.-1_2del (p.Met1del) AND Juvenile polyposis syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 5, 2018
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:: RCV002235788.13

Allele description [Variation Report for NM_004329.3(BMPR1A):c.-1_2del (p.Met1del)]

NM_004329.3(BMPR1A):c.-1_2del (p.Met1del)

Gene:

BMPR1A:bone morphogenetic protein receptor type 1A [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

10q23.2

Genomic location:

Preferred name:

NM_004329.3(BMPR1A):c.-1_2del (p.Met1del)

HGVS:

NC_000010.11:g.86876018_86876020del
NG_009362.1:g.124380_124382del
NM_004329.3:c.-1_2delMANE SELECT
NP_004320.2:p.Met1del
NP_004320.2:p.Met1del
LRG_298t1:c.-1_2del
LRG_298:g.124380_124382del
LRG_298p1:p.Met1del
NC_000010.10:g.88635775_88635777del
NM_004329.2:c.-1_2del

Protein change:

M1del

Links:

dbSNP: rs1589757037

NCBI 1000 Genomes Browser:

rs1589757037

Molecular consequence:

NM_004329.3:c.-1_2del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_004329.3:c.-1_2del - initiator_codon_variant - [Sequence Ontology: SO:0001582]

Condition(s)

Name:: Juvenile polyposis syndrome (JPS)
Synonyms:: Polyposis juvenile intestinal; Polyposis familial of entire gastrointestinal tract
Identifiers:: MONDO: MONDO:0017380; MedGen: C0345893; Orphanet: 2929; OMIM: 174900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000948858	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 5, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23433720, 18823382, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000948858

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 5, 2018)

germline

clinical testing

PubMed (3)
[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

BMPR1A mutations in juvenile polyposis affect cellular localization.

Howe JR, Dahdaleh FS, Carr JC, Wang D, Sherman SK, Howe JR.

J Surg Res. 2013 Oct;184(2):739-45. doi: 10.1016/j.jss.2013.01.015. Epub 2013 Feb 1.

PubMed [citation]

PMID:: 23433720
PMCID:: PMC3683109

The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis.

Calva-Cerqueira D, Chinnathambi S, Pechman B, Bair J, Larsen-Haidle J, Howe JR.

Clin Genet. 2009 Jan;75(1):79-85. doi: 10.1111/j.1399-0004.2008.01091.x. Epub 2008 Sep 24.

PubMed [citation]

PMID:: 18823382

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000948858.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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. While this variant is expected to result in an absent protein product, possible rescue of translational initiation by the downstream methionine would lead to the disruption of the signal peptide (residues 1-23), which appears critical for BMPR1A-mediated cellular localization (PMID: 23433720). Also, different variants (c.1A>C, c.1A>G) giving rise to a similar protein effect observed here (initiator codon) has been reported in individuals affected with juvenile polyposis syndrome (PMID: 18823382, Invitae), indicating that this residue may be critical for protein function. This variant has not been reported in the literature in individuals with BMPR1A-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the BMPR1A mRNA. The next in-frame methionine is located at codon 29.

#	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: Nov 3, 2024

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