rs1553345934

Positions:

• chr1-210804124-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_172362.3(KCNH1):​c.1505T>C​(p.Phe502Ser) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH1 NM_172362.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.99

Genes affected

KCNH1 (HGNC:6250): (potassium voltage-gated channel subfamily H member 1) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNH1. . Gene score misZ 3.8156 (greater than the threshold 3.09). Trascript score misZ 5.0674 (greater than threshold 3.09). GenCC has associacion of gene with KCNH1 associated disorder, Zimmermann-Laband syndrome, Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH1	NM_172362.3	c.1505T>C	p.Phe502Ser	missense_variant	8/11	ENST00000271751.10	NP_758872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH1	ENST00000271751.10	c.1505T>C	p.Phe502Ser	missense_variant	8/11	2	NM_172362.3	ENSP00000271751

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2022

The c.1505T>C (p.F502S) alteration is located in coding exon 8 of the KCNH1 gene. This alteration results from a T to C substitution at nucleotide position 1505, causing the phenylalanine (F) at amino acid position 502 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The p.F502S amino acid is located in the S6 transmembrane domain. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;D;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;.;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	.;.;L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.7	D;.;D;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;D;.;.
Sift4G	Uncertain	0.0020	D;.;D;.;.
Polyphen		1.0	.;.;D;.;.
Vest4		0.90
MutPred		0.80		.;Gain of disorder (P = 0.0323);Gain of disorder (P = 0.0323);.;.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553345934; hg19: chr1-210977466;