11-2570710-T-C

Variant names:

• chr11-2570710-T-C
• rs199473399
• NM_000218.3:c.560T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000218.3(KCNQ1):​c.560T>C​(p.Leu187Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L187R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 O:1
• Conservation: PhyloP100: 5.84
• Publications: 7 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
• long QT syndrome 1

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

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 23 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2570710-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 843851.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 11-2570710-T-C is Pathogenic according to our data. Variant chr11-2570710-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53066.

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.560T>C	p.Leu187Pro	missense	Exon 3 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.560T>C	p.Leu187Pro	missense	Exon 3 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.290T>C	p.Leu97Pro	missense	Exon 4 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.560T>C	p.Leu187Pro	missense	Exon 3 of 16	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.179T>C	p.Leu60Pro	missense	Exon 3 of 16	ENSP00000334497.5
	KCNQ1	ENST00000910997.1		c.557T>C	p.Leu186Pro	missense	Exon 3 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249636 AF XY: 0.00000739

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460180 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726478

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000990 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
1	-	-	Long QT syndrome (1)
1	-	-	Long QT syndrome 1 (1)
-	1	-	not provided (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
CardioboostArm	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Benign	0.027
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.9	L
PhyloP100		5.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.77
Sift	Benign	0.18	T
Sift4G	Benign	0.33	T
Polyphen		0.047	B
Vest4		0.90
MutPred		0.92		Loss of stability (P = 0.0531)
MVP		0.96
MPC		0.63
ClinPred		0.82	D
GERP RS		4.4
Varity_R		0.88
gMVP		0.97
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs199473399; hg19: chr11-2591940;