rs199473485

Variant names:

• chr11-2445100-T-A
• rs199473485
• NM_000218.3:c.2T>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2445100-T-A
• chr11-2445100-T-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PS3 PM2 PP5_Moderate

The NM_000218.3(KCNQ1):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000680796: Additional functional studies showed that while the c.2 T>C variant does not demonstrate a dominant negative effect when co-expressed with wild type protein, it does result in loss of function of the KCNQ1 channel due to a trafficking defect (Wang et al., 2011).". The gene KCNQ1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.379
• Publications: 4 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: 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: 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

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 69 pathogenic variants. Next in-frame start position is after 159 codons. Genomic position: 2528016. Lost 0.234 part of the original CDS.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000680796: Additional functional studies showed that while the c.2 T>C variant does not demonstrate a dominant negative effect when co-expressed with wild type protein, it does result in loss of function of the KCNQ1 channel due to a trafficking defect (Wang et al., 2011).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2445100-T-A is Pathogenic according to our data. Variant chr11-2445100-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 488859.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2T>A	p.Met1?	start_lost	Exon 1 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 15	NP_001393765.1
	KCNQ1	NM_001406838.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 11	NP_001393767.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000910997.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 16	ENSP00000581056.1
	KCNQ1	ENST00000713725.1		c.2T>A	p.Met1?	start_lost	Exon 1 of 15	ENSP00000519029.1	A0AAQ5BGS5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 936200 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 440548

African (AFR) AF: 0.00 AC: 0 AN: 17860

American (AMR) AF: 0.00 AC: 0 AN: 4012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8250

East Asian (EAS) AF: 0.00 AC: 0 AN: 12916

South Asian (SAS) AF: 0.00 AC: 0 AN: 19942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2096

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826614

Other (OTH) AF: 0.00 AC: 0 AN: 33098

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.046	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.91	D
PhyloP100		0.38
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.084	B
Vest4		0.39
MutPred		0.96		Gain of ubiquitination at M1 (P = 0.0177)
MVP		0.95
ClinPred		0.79	D
GERP RS		2.1
PromoterAI		0.056	Neutral
Varity_R		0.91
gMVP		0.67
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs199473485; hg19: chr11-2466330;