7-150974897-C-G

Position:

• chr7-150974897-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_000238.4(KCNH2):​c.121G>C​(p.Val41Leu) variant causes a missense 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.45

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

KCNH2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain PAS (size 29) in uniprot entity KCNH2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• PP5: Variant 7-150974897-C-G is Pathogenic according to our data. Variant chr7-150974897-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372589.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.121G>C	p.Val41Leu	missense_variant	2/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.121G>C	p.Val41Leu	missense_variant	2/15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000532957.5	n.344G>C		non_coding_transcript_exon_variant	2/9	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 09, 2015

While the V41L variant in theKCNH2 gene has not been reported to our knowledge, variants affecting this same residue (V41F and V41A)have been reported in association with LQTS (Kapplinger et al., 2009; Nagaoka et al., 2008). V41F has beenreported in one individual with LQTS and was absent in 2600 controls alleles and V41A has been reported inone individual of Japanese ancestry with LQTS (Kapplinger et al., 2009; Nagaoka et al., 2008). Variants innearby residues (R35W, C39R, I42N, Y43D, Y43C) have also been reported in HGMD in association withLQTS (Stenson P et al., 2014), further supporting the functional importance of this region of the protein. TheV41L variant is a conservative amino acid substitution at a position that is conserved among mammals.Furthermore, the V41L variant was not observed in approximately 6500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant inthese populations.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is abenign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	-0.21	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.60
Sift	Benign	0.039	D
Sift4G	Uncertain	0.027	D
Polyphen		0.0	B
Vest4		0.56
MutPred		0.72		Loss of catalytic residue at V41 (P = 0.0429);
MVP		0.97
MPC		1.0
ClinPred		0.81	D
GERP RS		4.1
Varity_R		0.79
gMVP		0.93

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: rs199472835; hg19: chr7-150671985;