ClinVar Genomic variation as it relates to human health
NM_000218.3(KCNQ1):c.958C>T (p.Pro320Ser)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000218.3(KCNQ1):c.958C>T (p.Pro320Ser)
Variation ID: 67130 Accession: VCV000067130.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.5 11: 2583471 (GRCh38) [ NCBI UCSC ] 11: 2604701 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 1, 2016 May 1, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000218.3:c.958C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000209.2:p.Pro320Ser missense NM_001406836.1:c.958C>T NP_001393765.1:p.Pro320Ser missense NM_001406837.1:c.688C>T NP_001393766.1:p.Pro230Ser missense NM_001406838.1:c.514C>T NP_001393767.1:p.Pro172Ser missense NM_181798.2:c.577C>T NP_861463.1:p.Pro193Ser missense NR_040711.2:n.851C>T NC_000011.10:g.2583471C>T NC_000011.9:g.2604701C>T NG_008935.1:g.143481C>T LRG_287:g.143481C>T LRG_287t1:c.958C>T LRG_287p1:p.Pro320Ser LRG_287t2:c.577C>T LRG_287p2:p.Pro193Ser P51787:p.Pro320Ser - Protein change
- P320S, P193S, P172S, P230S
- Other names
- p.P320S:CCC>TCC
- Canonical SPDI
- NC_000011.10:2583470:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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KCNQ1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
1717 | 2650 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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not provided (1) |
no classification provided
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- | RCV000057827.4 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 15, 2021 | RCV000182143.12 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000223841.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 24, 2023 | RCV000466144.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 5, 2019 | RCV002381371.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2022 | RCV002468561.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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. |
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Likely pathogenic
(Mar 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713553.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS4_Moderate, PM2, PM5, PP3
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002765086.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
_x000D_ Criteria applied: PS4_MOD, PM1, PM5, PM2_SUP, PP3
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Likely pathogenic
(Nov 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000234446.12
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); At the protein level, silico analysis supports that this missense variant has … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); At the protein level, silico analysis supports that this missense variant has a deleterious effect on protein structure/function; At the mRNA level, in-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar (ClinVar Variant ID# 67130; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19716085, 22581653, 23392653, 19540844, 26669661, 29033053, 27041150, 32383558) (less)
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Likely pathogenic
(Jun 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002694926.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P320S variant (also known as c.958C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide … (more)
The p.P320S variant (also known as c.958C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 958. The proline at codon 320 is replaced by serine, an amino acid with similar properties, and is located in the pore domain. This variant was detected in an individual with prolonged QT, who also had an additional KCNQ1 variant detected, as well as in her affected son who had prolonged QT and only this variant (Giudicessi JR et al. Circ Cardiovasc Genet, 2013 Apr;6:193-200). In a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data, Sun J et al. Cell, 2017 Jun;169:1042-1050.e9). Alternate amino acid substitutions at this codon, p.P320A and p.P320H, have also been reported in LQTS cohorts, and functional studies supported a dominant negative impact for both variants (Donger C et al. Circulation, 1997 Nov;96:2778-81; Thomas D et al. J. Mol. Cell. Cardiol., 2010 Jan;48:230-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Sep 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598582.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: KCNQ1 c.958C>T (p.Pro320Ser) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of … (more)
Variant summary: KCNQ1 c.958C>T (p.Pro320Ser) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 253994 control chromosomes. c.958C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome. These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000543308.5
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 320 of the KCNQ1 protein (p.Pro320Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 320 of the KCNQ1 protein (p.Pro320Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 23392653; Invitae). ClinVar contains an entry for this variant (Variation ID: 67130). 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 KCNQ1 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro320 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19540844, 22949429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280168.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Pro320Ser Given the weak case data and minimal controls, we consider this variant a variant of uncertain significance, probably disease causing. The variant has been seen in at least one unrelated cases of long QT syndrome (not including this patient's family), possibly two. There is weak segregation data. The variant was reported in one individual in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Ancestry was not provided. Ackerman's group later reported a patient seen in their Mayo LQTS clinic who was a compound heterozygote for this variant and p.Pro448Leu (Giudicessi et al 2013). The patient was a female with a QTc of 499 ms, one syncopal episode, and normal hearing. Several family members who carry just p.Pro448Leu had normal QTc measurements while the proband's son carried just p.Pro320Ser and had a QTc of 505 ms. Ancestry was not provided. That case may overlap with Kapplinger et al (2009) as some of the patients had commercial genetic testing. Unfortunately insufficient information is provided in Kapplinger et al (2009) to determine if it is in fact the same case. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar score 1.000). The proline at codon 320 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Pro320Ala, p.Pro320His) and nearby codons (p.Val310Asn, p.Val310Ile, p.Gly314Asn, p.Gly314Arg, p.Gly314Ser, p.Gly316Glu, p.Gly316Arg, p.Gly316Val, p.Gly316Val, p.Lys318Asn, p.Thr322Ala, p.Thr322Lys, p.Thr322Met, p.Gly325Arg, p.Gly325Glu, p.Gly325Trp). In total the variant has not been seen in ~9800 published controls and individuals from publicly available population datasets. There is no variation at codon 320 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 8th, 2014). The variant is listed in dbSNP (rs199472753), however the only submission is a locus specific database noting reports with disease in the literature. The variant was not observed in the following published control samples: 1300 ostensibly healthy individuals (Kapplinger et al 2009). (less)
Number of individuals with the variant: 2
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not provided
(-)
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no classification provided
Method: literature only
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Congenital long QT syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089347.3
First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016 |
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily … (more)
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region. | Schwartz PJ | European heart journal | 2021 | PMID: 34505893 |
Reclassification of genetic variants in children with long QT syndrome. | Westphal DS | Molecular genetics & genomic medicine | 2020 | PMID: 32383558 |
Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome. | Sun J | Cell | 2017 | PMID: 28575668 |
Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity. | Giudicessi JR | Circulation. Cardiovascular genetics | 2013 | PMID: 23392653 |
Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. | Giudicessi JR | Circulation. Cardiovascular genetics | 2012 | PMID: 22949429 |
Biophysical characterization of KCNQ1 P320 mutations linked to long QT syndrome 1. | Thomas D | Journal of molecular and cellular cardiology | 2010 | PMID: 19540844 |
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. | Kapplinger JD | Heart rhythm | 2009 | PMID: 19716085 |
Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. | Moss AJ | Circulation | 2007 | PMID: 17470695 |
KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. | Donger C | Circulation | 1997 | PMID: 9386136 |
Text-mined citations for rs199472753 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.