11-2847860-C-G

Variant names:

• chr11-2847860-C-G
• rs199472822
• NM_000218.3:c.1888C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000218.3(KCNQ1):​c.1888C>G​(p.Pro630Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,424,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. P630S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: -0.750
• Publications: 0 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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32136607).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1888C>G	p.Pro630Ala	missense	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1792C>G	p.Pro598Ala	missense	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1618C>G	p.Pro540Ala	missense	Exon 17 of 17	NP_001393766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1888C>G	p.Pro630Ala	missense	Exon 16 of 16	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.1507C>G	p.Pro503Ala	missense	Exon 16 of 16	ENSP00000334497.5
	KCNQ1	ENST00000713725.1		c.1747C>G	p.Pro583Ala	missense	Exon 15 of 15	ENSP00000519029.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1424256 Hom.: 0 Cov.: 31 AF XY: 0.00000284 AC XY: 2 AN XY: 705036

African (AFR) AF: 0.00 AC: 0 AN: 32672

American (AMR) AF: 0.00 AC: 0 AN: 40108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25434

East Asian (EAS) AF: 0.00 AC: 0 AN: 37578

South Asian (SAS) AF: 0.00 AC: 0 AN: 81418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1093082

Other (OTH) AF: 0.00 AC: 0 AN: 58886

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 630 of the KCNQ1 protein (p.Pro630Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT Syndrome (PMID: 17905336). ClinVar contains an entry for this variant (Variation ID: 53024). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNQ1 protein function with a negative predictive value of 95%. 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.

Congenital long QT syndrome Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:17905336). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
CardioboostArm	Benign	0.0025
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	5.8
DANN	Benign	0.70
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.43	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.32	T
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.5	L
PhyloP100		-0.75
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.60
Sift	Benign	0.054	T
Sift4G	Benign	0.090	T
Polyphen		0.96	D
Vest4		0.65
MutPred		0.65		Loss of glycosylation at P630 (P = 0.0196)
MVP		0.83
MPC		0.36
ClinPred		0.026	T
GERP RS		0.074
Varity_R		0.029
gMVP		0.47
Mutation Taster		=20/80	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: rs199472822; hg19: chr11-2869090;