NM_000218.3:c.1927G>T

Variant names:

• chr11-2847899-G-T
• rs1800172
• NM_000218.3:c.1927G>T
• KCNQ1 p.Gly643Cys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000218.3(KCNQ1):c.1927G>T (p.Gly643Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G643D: Uncertain_significance (ClinVar VariationId 923434, 1 star); p.G643S: Benign (ClinVar VariationId 36437, 3 stars)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.71
• Publications: 50 publications found

Genes affected

KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

KCNQ1 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• long QT syndrome 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• familial hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: G2P
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNQ1-AS1 (HGNC:42790): ()

Classification according to ACMG Germline Pathogenicity v2019

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.00022 by highest known P/LP ClinVar AF 0.00022) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNQ1 NM_000218.3	MANE Select	c.1927G>T p.Gly643Cys	missense	Exon 16 of 16	Prot: NP_000209.2
	KCNQ1 NM_001406836.1		c.1831G>T p.Gly611Cys	missense	Exon 15 of 15	Prot: NP_001393765.1
	KCNQ1 NM_001406837.1		c.1657G>T p.Gly553Cys	missense	Exon 17 of 17	Prot: NP_001393766.1

KCNQ1 NM_000218.3

MANE Select

HGVSc / HGVSpc.1927G>Tp.Gly643Cys

Exon rankExon 16 of 16

missense

Prot: NP_000209.2

KCNQ1 NM_001406836.1

HGVSc / HGVSpc.1831G>Tp.Gly611Cys

Exon rankExon 15 of 15

missense

Prot: NP_001393765.1

KCNQ1 NM_001406837.1

HGVSc / HGVSpc.1657G>Tp.Gly553Cys

Exon rankExon 17 of 17

missense

Prot: NP_001393766.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNQ1 ENST00000155840.12	TSL:1MANE Select	c.1927G>T p.Gly643Cys	missense	Exon 16 of 16	Prot: ENSP00000155840.2 UniProt:
	KCNQ1 ENST00000335475.6	TSL:1	c.1546G>T p.Gly516Cys	missense	Exon 16 of 16	Prot: ENSP00000334497.5 UniProt:
	KCNQ1 ENST00000910997.1		c.1924G>T p.Gly642Cys	missense	Exon 16 of 16	Prot: ENSP00000581056.1 UniProt:

KCNQ1 ENST00000155840.12

TSL:1MANE Select

HGVSc / HGVSpc.1927G>Tp.Gly643Cys

Exon rankExon 16 of 16

missense

Prot: ENSP00000155840.2UniProt: P51787-1

KCNQ1 ENST00000335475.6

TSL:1

HGVSc / HGVSpc.1546G>Tp.Gly516Cys

Exon rankExon 16 of 16

missense

Prot: ENSP00000334497.5UniProt: P51787-2

KCNQ1 ENST00000910997.1

HGVSc / HGVSpc.1924G>Tp.Gly642Cys

Exon rankExon 16 of 16

missense

Prot: ENSP00000581056.1UniProt: A0ACI8SIJ2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:1428034	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:8	AN:250862	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
Turkish Variome	AF: 0.000198	AC:1	Hom:0	AN:4574	Cov:

Showing 6 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.24
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	0.41
CardioboostArm	Benign	0.000011
DANN	Benign	0.95
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
FuncVEP CTI	Benign	0.0064
GPN-Star LLR	N/A	-0.72
GPN-Star score	N/A	0.72
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	0.69	D
Mutation Taster	N/A	76/24	polymorphism
MutationAssessor	Benign	0.34	N
PhyloP100	Benign	-4.7
popEVE	Benign	-2.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.60
Sift	Benign	0.045	D
Sift4G	Uncertain	0.057	T
Varity_R	N/A	0.12
VESM-3B	Benign	-4.7

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1800172;

hg19: chr11-2869129;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar