rs199472819

Variant names:

• chr11-2847827-T-A
• rs199472819
• NM_000218.3:c.1855T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000218.3(KCNQ1):​c.1855T>A​(p.Leu619Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000353 in 1,416,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L619S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: -1.15
• Publications: 6 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-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1855T>A	p.Leu619Met	missense	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1759T>A	p.Leu587Met	missense	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1585T>A	p.Leu529Met	missense	Exon 17 of 17	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1855T>A	p.Leu619Met	missense	Exon 16 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1474T>A	p.Leu492Met	missense	Exon 16 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1852T>A	p.Leu618Met	missense	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 176852 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1416376 Hom.: 0 Cov.: 31 AF XY: 0.00000714 AC XY: 5 AN XY: 700482

African (AFR) AF: 0.00 AC: 0 AN: 32504

American (AMR) AF: 0.00 AC: 0 AN: 38632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25338

East Asian (EAS) AF: 0.00 AC: 0 AN: 37224

South Asian (SAS) AF: 0.00 AC: 0 AN: 80606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000459 AC: 5 AN: 1088436

Other (OTH) AF: 0.00 AC: 0 AN: 58634

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Atrial fibrillation, familial, 3 (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Jervell and Lange-Nielsen syndrome 1 (1)
-	1	-	Long QT syndrome (1)
-	1	-	Long QT syndrome 1 (1)
-	1	-	not provided (1)
-	1	-	Short QT syndrome type 2 (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
CardioboostArm	Benign	0.0020
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	6.8
DANN	Benign	0.81
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	0.20	N
PhyloP100		-1.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.55
Sift	Benign	0.13	T
Sift4G	Benign	0.25	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.72		Loss of catalytic residue at L619 (P = 0.033)
MVP		0.77
MPC		0.37
ClinPred		0.032	T
GERP RS		-5.9
Varity_R		0.23
gMVP		0.56
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs199472819; hg19: chr11-2869057;