NM_000218.3(KCNQ1):c.1861G>A (p.Gly621Ser) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 23, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000484989.10

Allele description [Variation Report for NM_000218.3(KCNQ1):c.1861G>A (p.Gly621Ser)]

NM_000218.3(KCNQ1):c.1861G>A (p.Gly621Ser)

Genes:

KCNQ1-AS1:KCNQ1 antisense RNA 1 [Gene - HGNC]
KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000218.3(KCNQ1):c.1861G>A (p.Gly621Ser)

HGVS:

NC_000011.10:g.2847833G>A
NG_008935.1:g.407843G>A
NM_000218.3:c.1861G>AMANE SELECT
NM_001406836.1:c.1765G>A
NM_001406837.1:c.1591G>A
NM_001406838.1:c.1321G>A
NM_001406839.1:c.373G>A
NM_181798.2:c.1480G>A
NP_000209.2:p.Gly621Ser
NP_000209.2:p.Gly621Ser
NP_001393765.1:p.Gly589Ser
NP_001393766.1:p.Gly531Ser
NP_001393767.1:p.Gly441Ser
NP_001393768.1:p.Gly125Ser
NP_861463.1:p.Gly494Ser
NP_861463.1:p.Gly494Ser
LRG_287t1:c.1861G>A
LRG_287t2:c.1480G>A
LRG_287:g.407843G>A
LRG_287p1:p.Gly621Ser
LRG_287p2:p.Gly494Ser
NC_000011.9:g.2869063G>A
NM_000218.2:c.1861G>A
NM_181798.1:c.1480G>A
NR_040711.2:n.1754G>A

Protein change:

G125S

Links:

dbSNP: rs199472820

NCBI 1000 Genomes Browser:

rs199472820

Molecular consequence:

NM_000218.3:c.1861G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.1765G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.1591G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406838.1:c.1321G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406839.1:c.373G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.1480G>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
SCV000568142	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Mar 22, 2017)	germline	clinical testing	Citation Link,
SCV002041510	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 23, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 14661677, 25447171, 29247119, 32268277, 32917565 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000568142

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Mar 22, 2017)

germline

clinical testing

Citation Link,

SCV002041510

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 23, 2021)

germline

clinical testing

PubMed (5)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome.

Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME.

Mayo Clin Proc. 2003 Dec;78(12):1479-87.

PubMed [citation]

PMID:: 14661677

Post-mortem genetic analysis in juvenile cases of sudden cardiac death.

Campuzano O, Sanchez-Molero O, Allegue C, Coll M, Mademont-Soler I, Selga E, Ferrer-Costa C, Mates J, Iglesias A, Sarquella-Brugada G, Cesar S, Brugada J, Castellà J, Medallo J, Brugada R.

Forensic Sci Int. 2014 Dec;245:30-7. doi: 10.1016/j.forsciint.2014.10.004. Epub 2014 Oct 14.

PubMed [citation]

PMID:: 25447171

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000568142.3

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

Description

The G621S variant in the KCNQ1 gene has been published in an 11-month-old male with sudden cardiac death during sleeping. However, this individual harbored several cardiogenetic variants, including a TTN variant predicted to be disease-causing (Campuzano et al.,2014). The G621S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Finally, although G621S is not observed at a significant frequency in large population cohorts, it has been reported as a rare control variant in at least one ostensibly healthy Black individual (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server; Ackerman et al., 2003; Kapa et al., 2009; Giudicessi et al., 2012).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002041510.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: KCNQ1 c.1861G>A (p.Gly621Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 151578 control chromosomes in the gnomAD v3.1.2 database, including 1 homozygote. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.1861G>A has been reported in the literature in individuals affected by sudden unexplained death and also in an individual affected with Long QT Syndrome (Campuzano_2014, Lin_2017, Campuzano_2020, Ripoll-Vera_2021), but it was also reported in an apparently healthy control (Ackerman_2003). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly 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

Last Updated: Oct 13, 2024

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