7-150974897-C-G

Variant names:

• chr7-150974897-C-G
• rs199472835
• NM_000238.4:c.121G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V41A) has been classified as Uncertain significance.

• 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
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000238.4
• 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 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• 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 CliVar as Likely_pathogenic. Clinvar id is 372589.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-150974897-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 372589.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-150974897-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 372589.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-150974897-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 372589.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-150974897-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 372589.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-150974897-C-G is described in CliVar 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 rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.121G>C	p.Val41Leu	missense_variant	Exon 2 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.121G>C	p.Val41Leu	missense_variant	Exon 2 of 15	1	NM_000238.4	ENSP00000262186.5
KCNH2	ENST00000713710.1	c.121G>C	p.Val41Leu	missense_variant	Exon 2 of 15			ENSP00000519013.1
KCNH2	ENST00000532957.5	n.344G>C		non_coding_transcript_exon_variant	Exon 2 of 9	2
KCNH2	ENST00000713700.1	n.79G>C		non_coding_transcript_exon_variant	Exon 2 of 9

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

Apr 09, 2015

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
CardioboostArm	Benign	0.035
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
PhyloP100		1.4
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
Mutation Taster		=39/61	disease causing (ClinVar)

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: rs199472835; hg19: chr7-150671985;