1-210804083-G-T

Variant names:

• chr1-210804083-G-T
• rs727502820
• NM_172362.3:c.1546C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_172362.3(KCNH1):​c.1546C>A​(p.Leu516Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L516F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH1 NM_172362.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.43
• Publications: 0 publications found

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]

KCNH1 Gene-Disease associations (from GenCC):

• KCNH1 associated disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen
• Temple-Baraitser syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Zimmermann-Laband syndrome 1

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Zimmermann-Laband syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-210804083-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 162521.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172362.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH1	NM_172362.3	MANE Select	c.1546C>A	p.Leu516Ile	missense	Exon 8 of 11	NP_758872.1	O95259-1
	KCNH1	NM_002238.4		c.1465C>A	p.Leu489Ile	missense	Exon 8 of 11	NP_002229.1	O95259-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH1	ENST00000271751.10	TSL:2 MANE Select	c.1546C>A	p.Leu516Ile	missense	Exon 8 of 11	ENSP00000271751.4	O95259-1
	KCNH1	ENST00000639952.1	TSL:1	c.1465C>A	p.Leu489Ile	missense	Exon 8 of 11	ENSP00000492697.1	O95259-2
	KCNH1	ENST00000640044.1	TSL:1	c.394C>A	p.Leu132Ile	missense	Exon 4 of 7	ENSP00000491434.1	A0A1W2PPA2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.083
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.3	L
PhyloP100		6.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.53
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.11	B
Vest4		0.39
MutPred		0.36		Gain of MoRF binding (P = 0.1503)
MVP		0.97
MPC		1.7
ClinPred		0.84	D
GERP RS		5.6
Varity_R		0.35
gMVP		0.90
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs727502820; hg19: chr1-210977425;