VCV003076029.1 - ClinVar

NM_000238.4(KCNH2):c.3054_3055insCCCCCCC (p.Thr1019fs)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000238.4(KCNH2):c.3054_3055insCCCCCCC (p.Thr1019fs)

Variation ID: 3076029 Accession: VCV003076029.1

Type and length

Insertion, 7 bp

Location

Cytogenetic: 7q36.1 7: 150947425-150947426 (GRCh38) [ NCBI UCSC ] 7: 150644513-150644514 (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	Apr 20, 2024	Apr 20, 2024	Jan 31, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000238.4:c.3054_3055insCCCCCCC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000229.1:p.Thr1019fs	frameshift
NM_001406753.1:c.2766_2767insCCCCCCC	NP_001393682.1:p.Thr923fs	frameshift
NM_172057.3:c.2034_2035insCCCCCCC	NP_742054.1:p.Thr679fs	frameshift
NR_176254.1:n.3275_3276insCCCCCCC		non-coding transcript variant
NR_176255.1:n.2148_2149insCCCCCCC		non-coding transcript variant
NC_000007.14:g.150947430_150947431insGGGGGGG
NC_000007.13:g.150644518_150644519insGGGGGGG
NG_008916.1:g.35501_35502insCCCCCCC
LRG_288:g.35501_35502insCCCCCCC
LRG_288t1:c.3049_3050insCCCCCCC	LRG_288p1:p.Thr1019Profs
LRG_288t3:c.2029_2030insCCCCCCC	LRG_288p3:p.Thr679Profs

... more HGVS ... less HGVS

Protein change

T1019fs, T679fs, T923fs

Other names

Canonical SPDI

NC_000007.14:150947425:GGGGG:GGGGGGGGGGGG

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

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.
KCNH2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3223	3309

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.
Congenital long QT syndrome	Likely pathogenic (1)	criteria provided, single submitter	Jan 31, 2017	RCV004018347.2

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.
Likely Pathogenic (Jan 31, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital long QT syndrome Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848033.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Thr1019fs variant in KCNH2 has not been previously reported in individuals with long QT syndrome. Data from large population studies is insufficient to assess … (more) The p.Thr1019fs variant in KCNH2 has not been previously reported in individuals with long QT syndrome. Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1019 and leads to a premature termination codon 102 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is associated with long QT syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Thr1019fs variant is likely pathogenic for long QT syndrome in an autosomal dominant manner based on its predicted impact to the protein. (less)

Comment:

The p.Thr1019fs variant in KCNH2 has not been previously reported in individuals with long QT syndrome. Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1019 and leads to a premature termination codon 102 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the KCNH2 gene is associated with long QT syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Thr1019fs variant is likely pathogenic for long QT syndrome in an autosomal dominant manner based on its predicted impact to the protein.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_000238.4(KCNH2):c.3054_3055insCCCCCCC (p.Thr1019fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...