VCV000279981.25 - ClinVar

NM_172362.3(KCNH1):c.1070G>A (p.Arg357Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(15)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_172362.3(KCNH1):c.1070G>A (p.Arg357Gln)

Variation ID: 279981 Accession: VCV000279981.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q32.2 1: 210920032 (GRCh38) [ NCBI UCSC ] 1: 211093374 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Feb 14, 2024	Apr 20, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_172362.3:c.1070G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_758872.1:p.Arg357Gln	missense
NM_002238.4:c.989G>A	NP_002229.1:p.Arg330Gln	missense
NC_000001.11:g.210920032C>T
NC_000001.10:g.211093374C>T
NG_029777.2:g.219084G>A

... more HGVS ... less HGVS

Protein change

R357Q, R330Q

Other names

Canonical SPDI

NC_000001.11:210920031:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10602773 dbSNP: rs886041300 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
KCNH1		No evidence available	No evidence available	GRCh38 GRCh37	723	748

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 22, 2022	RCV000354221.13
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 22, 2016	RCV000624249.2
Zimmermann-Laband syndrome 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 23, 2023	RCV001251120.4
Abnormal facial shape Intellectual disability, severe Seizure	Likely pathogenic (1)	no assertion criteria provided	-	RCV001003573.1
Temple-Baraitser syndrome	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 20, 2023	RCV001262681.3
Seizure	Pathogenic (1)	no assertion criteria provided	-	RCV002274967.1
KCNH1-related disorder	Pathogenic (1)	criteria provided, single submitter	Jan 20, 2020	RCV004547654.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Zimmermann-Laband syndrome 1 Affected status: yes Allele origin: de novo	Centogene AG - the Rare Disease Company Accession: SCV001426487.1 First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020	Publications: PubMed (1) PubMed: 32860008
Likely pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Temple-Baraitser syndrome Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440632.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Pathogenic (Mar 02, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329665.6 First in ClinVar: Dec 06, 2016 Last updated: Apr 17, 2019	Comment: Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more) Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32860008, 26264464, 26818738, 27267311, 28628100, 28867141, 31278258, 32581362, 33594261) (less)
Pathogenic (Apr 22, 2016)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741482.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (2) PubMed: 26264464‚ 26818738 Observation 1: Number of individuals with the variant: 1 Clinical Features: Seizures (present) , Muscular hypotonia (present) , Global developmental delay (present) , Synophrys (present) , Gastrostomy tube feeding in infancy (present) , Depressed nasal bridge … (more) Seizures (present) , Muscular hypotonia (present) , Global developmental delay (present) , Synophrys (present) , Gastrostomy tube feeding in infancy (present) , Depressed nasal bridge (present) , Smooth philtrum (present) , Pes planus (present) , Long foot (present) , Wide intermamillary distance (present) , Delayed myelination (present) (less) Sex: male Ethnicity/Population group: Caucasian Observation 2: Number of individuals with the variant: 1 Clinical Features: Muscular hypotonia (present) , Brain atrophy (present) , Status epilepticus (present) , Developmental regression (present) , Smooth philtrum (present) , Broad nasal tip (present) , … (more) Muscular hypotonia (present) , Brain atrophy (present) , Status epilepticus (present) , Developmental regression (present) , Smooth philtrum (present) , Broad nasal tip (present) , Long face (present) , Short nose (present) , Seizures (present) , Thin upper lip vermilion (present) , Delayed eruption of teeth (present) , Depressed nasal bridge (present) , Global developmental delay (present) (less) Sex: female Ethnicity/Population group: Hispanic
Pathogenic (Jan 20, 2020)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	KCNH1-related disorders Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV001251558.2 First in ClinVar: May 31, 2020 Last updated: Mar 04, 2023	Publications: PubMed (2) PubMed: 26818738‚ 26264464 Comment: The KCNH1 c.1070G>A (p.Arg357Gln) variant is a missense variant that has been reported in two studies, in which it is found in a heterozygous, de … (more) The KCNH1 c.1070G>A (p.Arg357Gln) variant is a missense variant that has been reported in two studies, in which it is found in a heterozygous, de novo state in five unrelated individuals with KCNH1-related disorders (Bramswig et al. 2015; Fukai et al. 2016). The clinical presentation of the affected individuals includes global developmental delay, epilepsy, neonatal hypotonia, nail aplasia/hypoplasia, broad thumbs or toes, long great toes, and craniofacial dysmorphism. The p.Arg357Gln variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Arg357Gln variant is classified as pathogenic for KCNH1-related disorders. (less)
Pathogenic (May 27, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: de novo	Laboratoire Génétique Moléculaire, CHRU TOURS Accession: SCV001760729.1 First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021	Clinical Features: Global developmental delay (present) , Seizure (present) , Hypoplastic thumbnail (present)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Temple-Baraitser syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002058524.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:26818738 PMID:26818738 Comment: The variant has been previously reported as de novo in a similarly affected individual (PMID: 26818738, PS2_S). Same nucleotide change resulting in same amino acid … (more) The variant has been previously reported as de novo in a similarly affected individual (PMID: 26818738, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279981, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.872, 3CNET: 0.808, PP3_P). A missense variant is a common mechanism associated with Temple-Baraitser syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Clinodactyly of the 5th finger (present) , Global developmental delay (present) , Long philtrum (present) , Midface retrusion (present) , Periorbital fullness (present) , Seizure … (more) Clinodactyly of the 5th finger (present) , Global developmental delay (present) , Long philtrum (present) , Midface retrusion (present) , Periorbital fullness (present) , Seizure (present) , Axial hypotonia (present) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Zimmermann-Laband syndrome 1 Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002820120.1 First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023	Comment: The missense variant p.R357Q in KCNH1 (NM_172362.3) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported in … (more) The missense variant p.R357Q in KCNH1 (NM_172362.3) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported in multiple unrelated individuals as a de novo variant (Fukai R et al,Bramswig NC et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic.The p.R357Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.R357Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 357 of KCNH1 is conserved in all mammalian species. The nucleotide c.1070 in KCNH1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Seizure (present) , Joint hyperflexibility (present) , Hypotonia (present) , Feeding difficulties in infancy (present) , Underdeveloped supraorbital ridges (present) , Low-set, posteriorly rotated ears … (more) Seizure (present) , Joint hyperflexibility (present) , Hypotonia (present) , Feeding difficulties in infancy (present) , Underdeveloped supraorbital ridges (present) , Low-set, posteriorly rotated ears (present) , Depressed nasal bridge (present) , Reduced tendon reflexes (present) , Myopathic facies (present) (less)
Pathogenic (Apr 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Temple-Baraitser syndrome Affected status: yes Allele origin: de novo	Duke University Health System Sequencing Clinic, Duke University Health System Accession: SCV003919068.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Zimmermann-Laband syndrome 1 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV003921064.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023	Comment: _x000D_ Criteria applied: PS2_VSTR, PS4, PM5, PM2_SUP, PP2, PP3
Pathogenic (Dec 22, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001581542.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 23020937‚ 26264464‚ 26818738 Comment: This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein … (more) This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNH1 protein function. ClinVar contains an entry for this variant (Variation ID: 279981). This missense change has been observed in individual(s) with KCNH1-related conditions (PMID: 23020937, 26264464, 26818738). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 357 of the KCNH1 protein (p.Arg357Gln). (less)
Likely pathogenic (-)	no assertion criteria provided Method: research	Seizure Intellectual disability, severe Abnormal facial shape Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001161934.1 First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020	Publications: PubMed (1) PubMed: 32581362 Number of individuals with the variant: 1 Sex: female
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958862.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001970932.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Seizure Affected status: yes Allele origin: de novo	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV002562811.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022
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Comment:

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32860008, 26264464, 26818738, 27267311, 28628100, 28867141, 31278258, 32581362, 33594261)

Comment:

The KCNH1 c.1070G>A (p.Arg357Gln) variant is a missense variant that has been reported in two studies, in which it is found in a heterozygous, de novo state in five unrelated individuals with KCNH1-related disorders (Bramswig et al. 2015; Fukai et al. 2016). The clinical presentation of the affected individuals includes global developmental delay, epilepsy, neonatal hypotonia, nail aplasia/hypoplasia, broad thumbs or toes, long great toes, and craniofacial dysmorphism. The p.Arg357Gln variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Arg357Gln variant is classified as pathogenic for KCNH1-related disorders.

Comment:

The variant has been previously reported as de novo in a similarly affected individual (PMID: 26818738, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000279981, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.872, 3CNET: 0.808, PP3_P). A missense variant is a common mechanism associated with Temple-Baraitser syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The missense variant p.R357Q in KCNH1 (NM_172362.3) causes the same amino acid change as a previously established pathogenic variant. This variant has been reported in multiple unrelated individuals as a de novo variant (Fukai R et al,Bramswig NC et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic.The p.R357Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.R357Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 357 of KCNH1 is conserved in all mammalian species. The nucleotide c.1070 in KCNH1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNH1 protein function. ClinVar contains an entry for this variant (Variation ID: 279981). This missense change has been observed in individual(s) with KCNH1-related conditions (PMID: 23020937, 26264464, 26818738). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 357 of the KCNH1 protein (p.Arg357Gln).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.	Bertoli-Avella AM	European journal of human genetics : EJHG	2021	PMID: 32860008
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
De novo KCNH1 mutations in four patients with syndromic developmental delay, hypotonia and seizures.	Fukai R	Journal of human genetics	2016	PMID: 26818738
'Splitting versus lumping': Temple-Baraitser and Zimmermann-Laband Syndromes.	Bramswig NC	Human genetics	2015	PMID: 26264464
Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study.	Rauch A	Lancet (London, England)	2012	PMID: 23020937

Text-mined citations for rs886041300 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_172362.3(KCNH1):c.1070G>A (p.Arg357Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886041300 ...