11-2585212-G-A

Position:

• chr11-2585212-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000218.3(KCNQ1):​c.1033G>A​(p.Gly345Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G345E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense, splice_region
• Scores: Splicing: ADA: 0.5854
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.50

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.

• PM1: In a helix (size 19) in uniprot entity KCNQ1_HUMAN there are 35 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 chr11-2585213-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-2585212-G-A is Pathogenic according to our data. Variant chr11-2585212-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 200837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-2585212-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1033G>A	p.Gly345Arg	missense_variant, splice_region_variant	8/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1033G>A	p.Gly345Arg	missense_variant, splice_region_variant	8/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.652G>A	p.Gly218Arg	missense_variant, splice_region_variant	8/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.771+1667G>A		intron_variant		5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.588+1667G>A		intron_variant				ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Dec 09, 2013

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Gly345Arg This variant has previously been reported multiple times, in at least 2 (but likely more) unrelated individuals with LQTS, and also in another LQTS patient at LPCH. There is good published segregation data. Zareba et al. (2003) reported Gly345Arg in 12 subjects (from an unknown number of families, which we conservatively estimate as “one” family) from the International Long QT Syndrome Registry. Clinical information on these individuals was not provided, nor was information about the segregation of this variant with disease within the families. Van den Berg et al. (1997) reported a G>C substitution that results in the same Gly345Arg protein change (they report it as Gly216Arg, using alternate nomenclature). They identified the variant in a Dutch family where it segregated with LQTS in 5 symptomatic relatives across 4 generations. The proband in the family was a boy who died suddenly at age 9 during exercise. Multiple family members had a history of syncope. Variation at this and several nearby residues has been associated with LQT1, suggesting the functional importance of this codon and this protein region: 339delF; F339Y; A341E; A341V; A341G; L342F; P343S; P343L; P343R; A344V; A344E; A344A; A344 spice errors; G345E; S349W; S349X; S349P; G350R; F351S; L353P; K354R (UniProtKB; IRCCS Fondazione Salvatore Maugeri database). This is a non-conservative amino acid change, resulting in the replacement of a non-polar glycine with a basic, positively-charged arginine with a much larger side chain. The glycine at this location is highly conserved across 29 mammalian species, differing only in hedgehog. It lies in a region of remarkable evolutionary conservation: Dozens of amino acid residues to either side are almost 100% conserved across all 29 species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. According to 1000 Genomes, SIFT ranks it as “deleterious”. In total the variant has not been seen in >5350 published controls and individuals from publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals. No non-clinical variation at this residue is found in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP; among clinical variants it is rs120074183). It is not found in 1000 genomes (http://browser.1000genomes.org/index.htm) as of May 13, 2012. The variant was not observed in published controls: van den Berg et al. (1997) did not find the variant in 50 controls. Zareba et al. (2003) did not report controls. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 345 of the KCNQ1 protein (p.Gly345Arg). 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: 8528244, 9272155, 10220144, 14678125, 24762593, 26496715; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 200837). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.94		Gain of MoRF binding (P = 0.0238);.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473471; hg19: chr11-2606442;