NM_006172.4(NPPA):c.413T>C (p.Ile138Thr) AND Atrial fibrillation, familial, 6

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 4, 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:: RCV001870331.6

Allele description [Variation Report for NM_006172.4(NPPA):c.413T>C (p.Ile138Thr)]

NM_006172.4(NPPA):c.413T>C (p.Ile138Thr)

Genes:

NPPA-AS1:NPPA antisense RNA 1 [Gene - HGNC]
LOC114827827:VISTA enhancer hs2123 [Gene]
NPPA:natriuretic peptide A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.22

Genomic location:

Preferred name:

NM_006172.4(NPPA):c.413T>C (p.Ile138Thr)

HGVS:

NC_000001.11:g.11847150A>G
NG_012926.1:g.5634T>C
NG_065183.1:g.432A>G
NM_006172.4:c.413T>CMANE SELECT
NP_006163.1:p.Ile138Thr
LRG_751:g.5634T>C
NC_000001.10:g.11907207A>G

Protein change:

I138T

Links:

dbSNP: rs762638785

NCBI 1000 Genomes Browser:

rs762638785

Molecular consequence:

NM_006172.4:c.413T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Atrial fibrillation, familial, 6 (ATFB6)
Identifiers:: MONDO: MONDO:0012816; MedGen: C2677294; OMIM: 612201

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002119251	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 4, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31034774, 20064500, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002119251

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 4, 2023)

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

Mutation in NPPA causes atrial fibrillation by activating inflammation and cardiac fibrosis in a knock-in rat model.

Cheng C, Liu H, Tan C, Tong D, Zhao Y, Liu X, Si W, Wang L, Liang L, Li J, Wang C, Chen Q, Du Y, Wang QK, Ren X.

FASEB J. 2019 Aug;33(8):8878-8891. doi: 10.1096/fj.201802455RRR. Epub 2019 Apr 29.

PubMed [citation]

PMID:: 31034774

Identification of NPPA variants associated with atrial fibrillation in a Chinese GeneID population.

Ren X, Xu C, Zhan C, Yang Y, Shi L, Wang F, Wang C, Xia Y, Yang B, Wu G, Wang P, Li X, Wang D, Xiong X, Liu J, Liu Y, Liu M, Liu J, Tu X, Wang QK.

Clin Chim Acta. 2010 Apr 2;411(7-8):481-5. doi: 10.1016/j.cca.2009.12.019. Epub 2010 Jan 11.

PubMed [citation]

PMID:: 20064500

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002119251.3

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 138 of the NPPA protein (p.Ile138Thr). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects NPPA function (PMID: 31034774). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1356904). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 20064500). This variant is present in population databases (rs762638785, gnomAD 0.03%).

#	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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