NM_172362.3(KCNH1):c.1070G>A (p.Arg357Gln) AND Zimmermann-Laband syndrome 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001251120.4

Allele description [Variation Report for NM_172362.3(KCNH1):c.1070G>A (p.Arg357Gln)]

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

Gene:

KCNH1:potassium voltage-gated channel subfamily H member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q32.2

Genomic location:

Preferred name:

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

HGVS:

NC_000001.11:g.210920032C>T
NG_029777.2:g.219084G>A
NM_002238.4:c.989G>A
NM_172362.3:c.1070G>AMANE SELECT
NP_002229.1:p.Arg330Gln
NP_758872.1:p.Arg357Gln
NC_000001.10:g.211093374C>T
NG_029777.1:g.219084G>A
NM_172362.2:c.1070G>A

Protein change:

R330Q

Links:

dbSNP: rs886041300

NCBI 1000 Genomes Browser:

rs886041300

Molecular consequence:

NM_002238.4:c.989G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172362.3:c.1070G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Zimmermann-Laband syndrome 1 (ZLS1)
Synonyms:: Laband syndrome; Gingival fibromatosis, abnormal fingers, fingernails, nose and ears, and splenomegaly; Fibromatosis gingival, hepatosplenomegaly other anomalies
Identifiers:: MONDO: MONDO:0024526; MedGen: C4551773; Orphanet: 3473; OMIM: 135500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001426487	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32860008
SCV002820120	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003921064	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001426487

Centogene AG - the Rare Disease Company

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

de novo

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002820120

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003921064

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 23, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, et al.

Eur J Hum Genet. 2021 Jan;29(1):141-153. doi: 10.1038/s41431-020-00713-9. Epub 2020 Aug 28.

PubMed [citation]

PMID:: 32860008
PMCID:: PMC7852664

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Centogene AG - the Rare Disease Company, SCV001426487.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV002820120.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV003921064.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

_x000D_ Criteria applied: PS2_VSTR, PS4, PM5, PM2_SUP, PP2, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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