NM_004329.3(BMPR1A):c.1327C>T (p.Arg443Cys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Feb 6, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000586369.22

Allele description [Variation Report for NM_004329.3(BMPR1A):c.1327C>T (p.Arg443Cys)]

NM_004329.3(BMPR1A):c.1327C>T (p.Arg443Cys)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.2

Genomic location:

Preferred name:

NM_004329.3(BMPR1A):c.1327C>T (p.Arg443Cys)

Other names:

p.R443C:CGT>TGT

HGVS:

NC_000010.11:g.86921680C>T
NG_009362.1:g.170042C>T
NM_004329.3:c.1327C>TMANE SELECT
NP_004320.2:p.Arg443Cys
NP_004320.2:p.Arg443Cys
LRG_298t1:c.1327C>T
LRG_298:g.170042C>T
LRG_298p1:p.Arg443Cys
NC_000010.10:g.88681437C>T
NM_004329.2:c.1327C>T
P36894:p.Arg443Cys
p.R443C

Protein change:

R443C

Links:

UniProtKB: P36894#VAR_022831; dbSNP: rs35619497

NCBI 1000 Genomes Browser:

rs35619497

Molecular consequence:

NM_004329.3:c.1327C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000209877	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Jan 26, 2021)	germline	clinical testing	Citation Link,
SCV000600214	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Benign (Feb 6, 2023)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 32522261, 25637381, 15235019, 12417513, 18823382, 23399955, 25058500, 23433720, 24728327, 24055113, 27146957, 25980754, 14526373, 26976419, 28660566, 26467025
SCV000698311	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (May 27, 2016)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 26976419, 23399955, 24728327, 18823382, 25637381, 15235019, 12417513, 23433720, 25058500, 25980754 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV002009874	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004127022	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Nov 1, 2022)	germline	clinical testing	Citation Link

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
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection.

Velázquez C, Lastra E, Avila Cobos F, Abella L, de la Cruz V, Hernando BA, Hernández L, Martínez N, Infante M, Durán M.

J Transl Med. 2020 Jun 10;18(1):232. doi: 10.1186/s12967-020-02391-z.

PubMed [citation]

PMID:: 32522261
PMCID:: PMC7288470

Actionable, pathogenic incidental findings in 1,000 participants' exomes.

Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, Bennett RL, Jones KL, Tokita MJ, Bennett JT, Kim JH, Rosenthal EA, Kim DS; National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project., Tabor HK, Bamshad MJ, Motulsky AG, Scott CR, Pritchard CC, Walsh T, Burke W, Raskind WH, et al.

Am J Hum Genet. 2013 Oct 3;93(4):631-40. doi: 10.1016/j.ajhg.2013.08.006. Epub 2013 Sep 19.

PubMed [citation]

PMID:: 24055113
PMCID:: PMC3791261

See all PubMed Citations (17)

Details of each submission

From GeneDx, SCV000209877.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31968564, 28135145, 23399955, 25980754, 15235019, 12417513, 18823382, 28944238, 28873162, 27146957, 28660566, 25637381, 24728327, 24055113, 26976419, 23433720, 25058500, 21153778, 32522605)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000600214.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698311.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Variant summary: The c.1327C>T in BMPR1A gene is a missense change that involves the alteration of a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.061%, predominantly in individuals of European and Latino origins (0.08% and 0.13%, respectively). These frequencies exceed the maximal expected allele frequency for a pathogenic variant in BMPR1A (0.0002%). The variant of interest has been reported via reputable database/clinical laboratories as VUS/Benign without evidence to independently evaluate. On the other hand, the variant was identified in JP pt, who reportedly carried a known germline pathogenic mutation in SMAD4 and functional studies showed that R443C expression and BMP signaling levels comparable to wild-type, but it was mislocalized in transfected cells. One other publication reports the variant to co-occur in a patient with a potential pathogenic MSH2 mutation, and an internal sample has a co-occurrence with a pathogenic PMS2 variant, c.2186_2187delTC (classified as pathogenic by LCA). Taken together, this variant has been classified as a Likely Benign.

#	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

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009874.3

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

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

From CeGaT Center for Human Genetics Tuebingen, SCV004127022.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

BMPR1A: PP3, BS1

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

Last Updated: Apr 15, 2024

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