NM_172362.3(KCNH1):c.1480A>G (p.Ile494Val) AND Zimmermann-Laband syndrome 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 1, 2015
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000185590.15

Allele description [Variation Report for NM_172362.3(KCNH1):c.1480A>G (p.Ile494Val)]

NM_172362.3(KCNH1):c.1480A>G (p.Ile494Val)

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.1480A>G (p.Ile494Val)

HGVS:

NC_000001.11:g.210804149T>C
NG_029777.2:g.334967A>G
NM_002238.4:c.1399A>G
NM_172362.3:c.1480A>GMANE SELECT
NP_002229.1:p.Ile467Val
NP_758872.1:p.Ile494Val
NC_000001.10:g.210977491T>C
NG_029777.1:g.334967A>G
NM_172362.2:c.1480A>G
O95259:p.Ile494Val

Protein change:

I467V; ILE467VAL

Links:

UniProtKB: O95259#VAR_072614; OMIM: 603305.0001; OMIM: 603305.0005; dbSNP: rs727502819

NCBI 1000 Genomes Browser:

rs727502819

Molecular consequence:

NM_002238.4:c.1399A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_172362.3:c.1480A>G - 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

Recent activity

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V-type proton ATPase subunit C 2 isoform b [Homo sapiens]
V-type proton ATPase subunit C 2 isoform b [Homo sapiens]
gi|47717098|ref|NP_653184.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000212228	Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità	no assertion criteria provided	pathogenic	de novo	not provided
SCV000238499	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000212228

Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità

no assertion criteria provided

pathogenic

de novo

not provided

SCV000238499

OMIM

no assertion criteria provided

Pathogenic
(Jun 1, 2015)

germline

literature only

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	de novo	not provided	not provided	not provided	not provided	2	not provided	not provided

Citations

PubMed

Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome.

Kortüm F, Caputo V, Bauer CK, Stella L, Ciolfi A, Alawi M, Bocchinfuso G, Flex E, Paolacci S, Dentici ML, Grammatico P, Korenke GC, Leuzzi V, Mowat D, Nair LD, Nguyen TT, Thierry P, White SM, Dallapiccola B, Pizzuti A, Campeau PM, Tartaglia M, et al.

Nat Genet. 2015 Jun;47(6):661-7. doi: 10.1038/ng.3282. Epub 2015 Apr 27.

PubMed [citation]

PMID:: 25915598

Details of each submission

From Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità, SCV000212228.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

Description

Converted during submission to Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	not provided	2	not provided	not provided		not provided	not provided	not provided	not provided

From OMIM, SCV000238499.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 12.75-year-old German girl (patient 1) and a 4.5-year-old Indian girl (patient 6) with Zimmermann-Laband syndrome (ZLS1; 135500), Kortum et al. (2015) identified heterozygosity for a de novo c.1399A-G transition (c.1399A-G, NM_002238.3) in the KCNH1 gene, resulting in an ile467-to-val (I467V) substitution (designation per short transcript/isoform 2) at a highly conserved residue in the S6 segment. The mutation was not found in the unaffected parents from either family or in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Patch-clamp studies in CHO cells demonstrated accelerated channel activation and slower deactivation with the I467V mutant compared to wildtype, indicating a gain-of-function effect.

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

Last Updated: Nov 3, 2024

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