rs199473442

Positions:

• chr11-2445103-C-G
• chr11-2445103-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP5_Moderate

The NM_000218.3(KCNQ1):​c.5C>G​(p.Ala2Gly) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.301

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2445103-C-T is described in Lovd as [Pathogenic].
• PP5: Variant 11-2445103-C-G is Pathogenic according to our data. Variant chr11-2445103-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431053.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.5C>G	p.Ala2Gly	missense_variant	1/16	ENST00000155840.12	NP_000209.2
KCNQ1	NM_001406836.1	c.5C>G	p.Ala2Gly	missense_variant	1/15		NP_001393765.1
KCNQ1	NM_001406838.1	c.5C>G	p.Ala2Gly	missense_variant	1/11		NP_001393767.1
KCNQ1	NM_001406837.1	c.-358C>G		5_prime_UTR_variant	1/17		NP_001393766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.5C>G	p.Ala2Gly	missense_variant	1/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000646564.2	c.5C>G	p.Ala2Gly	missense_variant	1/11			ENSP00000495806
KCNQ1	ENST00000496887.7	c.24-280C>G		intron_variant		5		ENSP00000434560

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 940006 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 442668

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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Biotechnology Research Center, Pasteur Institute of Iran

Jul 27, 2017

According to the ACMG standards and guidelines, the following evidences results in the likely pathogenic variant: Not reported in ExAC and 1000G project and in more than 1000 unrelated Iranian individuals (PM2) but known disease mutation at this position (HGMD ID: CM097076, ClinVar ID: 67091) (PM5) Co segregated with the disease in the family (PP1) Missense variants in KCNQ1 gene are a common mechanism of the LQT1 disease (PP2) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.36
Sift	Benign	0.65	T
Sift4G	Benign	0.53	T
Polyphen		0.032	B
Vest4		0.35
MutPred		0.24		Gain of MoRF binding (P = 0.1134);
MVP		0.90
MPC		1.2
ClinPred		0.37	T
GERP RS		1.7
Varity_R		0.034
gMVP		0.28

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: rs199473442; hg19: chr11-2466333;