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NM_006172.4(NPPA):c.190A>C (p.Ser64Arg) AND not specified

Germline classification:
Benign (2 submissions)
Last evaluated:
Dec 15, 2021
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:
RCV000780554.6

Allele description [Variation Report for NM_006172.4(NPPA):c.190A>C (p.Ser64Arg)]

NM_006172.4(NPPA):c.190A>C (p.Ser64Arg)

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.190A>C (p.Ser64Arg)
HGVS:
  • NC_000001.11:g.11847373T>G
  • NG_012926.1:g.5411A>C
  • NG_065183.1:g.655T>G
  • NM_006172.4:c.190A>CMANE SELECT
  • NP_006163.1:p.Ser64Arg
  • LRG_751t1:c.190A>C
  • LRG_751:g.5411A>C
  • NC_000001.10:g.11907430T>G
  • NM_006172.3:c.190A>C
Protein change:
S64R; SER64ARG
Links:
OMIM: 108780.0002; dbSNP: rs61757261
NCBI 1000 Genomes Browser:
rs61757261
Molecular consequence:
  • NM_006172.4:c.190A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000917915Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Benign
(Dec 15, 2021)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV001978950Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Benigngermlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation.

Abraham RL, Yang T, Blair M, Roden DM, Darbar D.

J Mol Cell Cardiol. 2010 Jan;48(1):181-90. doi: 10.1016/j.yjmcc.2009.07.020. Epub 2009 Jul 30.

PubMed [citation]
PMID:
19646991
PMCID:
PMC2813326

Chromosome 4q25 variants are genetic modifiers of rare ion channel mutations associated with familial atrial fibrillation.

Ritchie MD, Rowan S, Kucera G, Stubblefield T, Blair M, Carter S, Roden DM, Darbar D.

J Am Coll Cardiol. 2012 Sep 25;60(13):1173-81. doi: 10.1016/j.jacc.2012.04.030. Epub 2012 Jul 18.

PubMed [citation]
PMID:
22818067
PMCID:
PMC3448817
See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917915.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

Variant summary: NPPA c.190A>C (p.Ser64Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 263016 control chromosomes, predominantly at a frequency of 0.0029 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 92.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPPA causing Atrial Fibrillation phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.190A>C has been reported in the literature in multiple individuals affected with Atrial Fibrillation and Arrythmia, but also in healthy controls (example: Abraham_2010, Ritchie_2012, Disertori_2012, Disertori_2016, Hertz_2014, Hertz_2016, Guelly_2020). Co-occurrences with other pathogenic variants have been reported (SCN5A c.361C>T / p.Arg121Trp, Hertz_2014; KCNH2 c.2587C>T / p.Arg863X, internal sample), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, reporting an increased potassium current associated with this variant (Abraham_2010). However, a case-control study reported that the variant was relatively common among non-AF controls, which suggested that it may not be causative i.e. the monogenic cause of AF, though it might be associated with very low penetrance or contribute in some as yet undefined fashion to AF susceptibility (Weeke_2015). Two ClinVar submitters have assessed this variant since 2014: one classified the variant as likely benign and the other as benign. Based on the evidence outlined above, the variant was classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001978950.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024