rs199473485

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 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 (★).

• 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• 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 id is 488859.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.2T>A	p.Met1?	start_lost	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.2T>A	p.Met1?	start_lost	1/15
KCNQ1	NM_001406838.1	c.2T>A	p.Met1?	start_lost	1/11
KCNQ1	NM_001406837.1	c.-361T>A		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.2T>A	p.Met1?	start_lost	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000646564.2	c.2T>A	p.Met1?	start_lost	1/11
KCNQ1	ENST00000496887.7	c.24-283T>A		intron_variant		5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 03, 2016

Although the c.2 T>A pathogenic variant in the KCNQ1 gene has not been published to our knowledge, another pathogenic variant affecting the same nucleotide, c.2 T>C, has been reported previously in association with JLNS and LQTS (Wang et al., 2011; Gao et al., 2016). Wang et al. (2011) reported c.2 T>C, situated on opposite KCNQ1 alleles (in trans) from a pathogenic frameshift variant, in one individual with JLNS. This individual's father, who was asymptomatic but had a borderline prolonged QTc interval, also harbored c.2 T>C (Wang et al., 2011). Subsequently, Gao et al (2015) identified c.2 T>C in three Chinese individuals with LQTS, and reported it was absent in at least 100 ethnically matched, healthy control alleles. Data from control individuals was not available to assess whether c.2 T>A may be a common benign variant in the general population. Both the c.2 T>A variant and the c.2 T>C variant alter the initiator Methionine residue of KCNQ1. Western blot studies showed that c.2 T>C may cause an alternate translation initiation site downstream and yields a truncated protein that is missing the initial 158 amino acid residues of the KCNQ1 protein (Wang et al., 2011). 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).In summary, c.2 T>A in the KCNQ1 gene is interpreted as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D
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
Varity_R		0.91
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs199473485; hg19: chr11-2466330;