11-2587606-T-G

Position:

• chr11-2587606-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000218.3(KCNQ1):​c.1165T>G​(p.Ser389Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S389P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a strand (size 5) in uniprot entity KCNQ1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr11-2587607-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2030049.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.1165T>G	p.Ser389Ala	missense_variant	9/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1165T>G	p.Ser389Ala	missense_variant	9/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.784T>G	p.Ser262Ala	missense_variant	9/16	1
KCNQ1	ENST00000496887.7	c.808T>G	p.Ser270Ala	missense_variant	9/16	5
KCNQ1	ENST00000646564.2	c.625T>G	p.Ser209Ala	missense_variant	4/11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 07, 2022

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 389 of the KCNQ1 protein (p.Ser389Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 574906). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.055
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Uncertain	0.60
Sift	Benign	0.24	T;.;T
Sift4G	Benign	0.57	T;.;T
Polyphen		0.32	B;.;B
Vest4		0.28
MutPred		0.41		Gain of helix (P = 0.0425);.;.;
MVP		0.95
MPC		0.53
ClinPred		0.87	D
GERP RS		4.7
Varity_R		0.64
gMVP		0.71

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: rs199472772; hg19: chr11-2608836;