NM_000218.3(KCNQ1):c.887T>C (p.Phe296Ser) AND Long QT syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 24, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001044347.9

Allele description [Variation Report for NM_000218.3(KCNQ1):c.887T>C (p.Phe296Ser)]

NM_000218.3(KCNQ1):c.887T>C (p.Phe296Ser)

Gene:

KCNQ1:potassium voltage-gated channel subfamily Q member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_000218.3(KCNQ1):c.887T>C (p.Phe296Ser)

HGVS:

NC_000011.10:g.2572952T>C
NG_008935.1:g.132962T>C
NM_000218.3:c.887T>CMANE SELECT
NM_001406836.1:c.887T>C
NM_001406837.1:c.617T>C
NM_181798.2:c.506T>C
NP_000209.2:p.Phe296Ser
NP_000209.2:p.Phe296Ser
NP_001393765.1:p.Phe296Ser
NP_001393766.1:p.Phe206Ser
NP_861463.1:p.Phe169Ser
NP_861463.1:p.Phe169Ser
LRG_287t1:c.887T>C
LRG_287t2:c.506T>C
LRG_287:g.132962T>C
LRG_287p1:p.Phe296Ser
LRG_287p2:p.Phe169Ser
NC_000011.9:g.2594182T>C
NM_000218.2:c.887T>C
NM_181798.1:c.506T>C
NR_040711.2:n.780T>C

Protein change:

F169S

Links:

dbSNP: rs199472738

NCBI 1000 Genomes Browser:

rs199472738

Molecular consequence:

NM_000218.3:c.887T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406836.1:c.887T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406837.1:c.617T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181798.2:c.506T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001208138	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 24, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19808498, 17470695, 21350584, 30847666, 28492532
SCV004817872	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 24, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17905336, 19808498, 21350584, 22456477, 26318259, 26669661, 32893267, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001208138

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 24, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004817872

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Feb 24, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene.

Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, Qi M, Vincent GM, Ackerman MJ, Kaufman ES, Hofman N, Seth R, Kamakura S, Miyamoto Y, Goldenberg I, Andrews ML, McNitt S.

Circulation. 2007 May 15;115(19):2481-9. Epub 2007 Apr 30.

PubMed [citation]

PMID:: 17470695
PMCID:: PMC3332528

Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.

van Lint FHM, Mook ORF, Alders M, Bikker H, Lekanne Dit Deprez RH, Christiaans I.

Neth Heart J. 2019 Jun;27(6):304-309. doi: 10.1007/s12471-019-1250-5.

PubMed [citation]

PMID:: 30847666
PMCID:: PMC6533346

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001208138.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect KCNQ1 protein function (PMID: 19808498). This variant has been observed in several individuals with clinical features of long QT syndrome (LQTS) (PMID: 19808498, 17470695, 21350584, 30847666, Invitae). ClinVar contains an entry for this variant (Variation ID: 67119). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 296 of the KCNQ1 protein (p.Phe296Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine.

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

From All of Us Research Program, National Institutes of Health, SCV004817872.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces phenylalanine with serine at codon 296 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in vitro functional study has shown that this variant causes a reduction in channel currents (PMID: 19808498). This variant has been reported in at least seven unrelated individuals affected with long QT syndrome (PMID: PMID: 17905336, 21350584, 22456477, 26318259, 26669661, 32893267). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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