NM_000218.3(KCNQ1):c.584G>A (p.Arg195Gln) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 5, 2019
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:: RCV001193175.9

Allele description [Variation Report for NM_000218.3(KCNQ1):c.584G>A (p.Arg195Gln)]

NM_000218.3(KCNQ1):c.584G>A (p.Arg195Gln)

Gene:

KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000218.3(KCNQ1):c.584G>A (p.Arg195Gln)

Other names:

p.R195Q:CGG>CAG

HGVS:

NC_000011.10:g.2570734G>A
NG_008935.1:g.130744G>A
NM_000218.3:c.584G>AMANE SELECT
NM_001406836.1:c.584G>A
NM_001406837.1:c.314G>A
NM_181798.2:c.203G>A
NP_000209.2:p.Arg195Gln
NP_000209.2:p.Arg195Gln
NP_001393765.1:p.Arg195Gln
NP_001393766.1:p.Arg105Gln
NP_861463.1:p.Arg68Gln
NP_861463.1:p.Arg68Gln
LRG_287t1:c.584G>A
LRG_287t2:c.203G>A
LRG_287:g.130744G>A
LRG_287p1:p.Arg195Gln
LRG_287p2:p.Arg68Gln
NC_000011.9:g.2591964G>A
NM_000218.2:c.584G>A
NM_181798.1:c.203G>A
NR_040711.2:n.477G>A

Protein change:

R105Q

Links:

dbSNP: rs138362632

NCBI 1000 Genomes Browser:

rs138362632

Molecular consequence:

NM_000218.3:c.584G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.584G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.203G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001361859	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 5, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19841300, 23861489, 29197658 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001361859

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 5, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.

Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, Wilde AA, Ackerman MJ.

Circulation. 2009 Nov 3;120(18):1752-60. doi: 10.1161/CIRCULATIONAHA.109.863076. Epub 2009 Oct 19.

PubMed [citation]

PMID:: 19841300
PMCID:: PMC3025752

Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening.

Zaydman MA, Silva JR, Delaloye K, Li Y, Liang H, Larsson HP, Shi J, Cui J.

Proc Natl Acad Sci U S A. 2013 Aug 6;110(32):13180-5. doi: 10.1073/pnas.1305167110. Epub 2013 Jul 16.

PubMed [citation]

PMID:: 23861489
PMCID:: PMC3740903

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361859.1

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

Description

Variant summary: The variant, KCNQ1 c.584G>A (p.Arg195Gln) results in a conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277966 control chromosomes (gnomAD and Kapa_2009). This frequency is not higher than expected for a pathogenic variant in KCNQ1 causing Arrhythmia (4e-05 vs 0.0001), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.584G>A in individuals affected with Arrhythmia has been reported. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated decreased whole-cell current amplitudes in Xenopus oocytes, however these results do not allow convincing conclusions about the variant effect (Zaydman_2013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2X uncertain significance, and 1X Likely Pathogenic). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Oct 8, 2024

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