ClinVar Genomic variation as it relates to human health
NM_001458.5(FLNC):c.4021C>T (p.Arg1341Ter)
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
-
NM_001458.5(FLNC):c.4021C>T (p.Arg1341Ter)
Variation ID: 620373 Accession: VCV000620373.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q32.1 7: 128846357 (GRCh38) [ NCBI UCSC ] 7: 128486411 (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 Mar 19, 2019 Mar 23, 2024 Mar 26, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001458.5:c.4021C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001449.3:p.Arg1341Ter nonsense NM_001127487.2:c.4021C>T NP_001120959.1:p.Arg1341Ter nonsense NC_000007.14:g.128846357C>T NC_000007.13:g.128486411C>T NG_011807.1:g.20929C>T LRG_870:g.20929C>T LRG_870t1:c.4021C>T LRG_870p1:p.Arg1341Ter - Protein change
- R1341*
- Other names
- -
- Canonical SPDI
- NC_000007.14:128846356:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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 | ||
---|---|---|---|---|---|---|
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. |
|||
FLNC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3113 | 4821 |
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. |
---|---|---|---|---|
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 21, 2018 | RCV000760746.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 26, 2023 | RCV001067745.12 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 26, 2022 | RCV001809795.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 23, 2020 | RCV002370018.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 24, 2021 | RCV003166019.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 13, 2022 | RCV003985093.1 |
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
(Sep 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000890640.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
Comment:
The R1341X variant in the FLNC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This … (more)
The R1341X variant in the FLNC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R1341X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R1341X as a likely pathogenic variant. (less)
|
|
Likely pathogenic
(Sep 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000927949.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 26
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058234.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000620373). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Left ventricular hypertrophy (present)
|
|
Pathogenic
(Dec 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Primary familial dilated cardiomyopathy
Affected status: yes
Allele origin:
inherited
|
Center for Human Genetics, University of Leuven
Accession: SCV002581947.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Number of individuals with the variant: 2
|
|
Pathogenic
(Nov 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002625542.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R1341* pathogenic mutation (also known as c.4021C>T), located in coding exon 23 of the FLNC gene, results from a C to T substitution at … (more)
The p.R1341* pathogenic mutation (also known as c.4021C>T), located in coding exon 23 of the FLNC gene, results from a C to T substitution at nucleotide position 4021. This changes the amino acid from an arginine to a stop codon within coding exon 23. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Sep 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 26
Affected status: unknown
Allele origin:
germline
|
New York Genome Center
Accession: SCV003925228.2
First in ClinVar: May 20, 2023 Last updated: Oct 21, 2023 |
Comment:
The c.4021C>T p.(Arg1341Ter) variant in the FLNC gene has previously been reported in an infant with dilated cardiomyopathy [PMID:31527676] and it has been deposited in … (more)
The c.4021C>T p.(Arg1341Ter) variant in the FLNC gene has previously been reported in an infant with dilated cardiomyopathy [PMID:31527676] and it has been deposited in ClinVar [ClinVar ID: 620373] as Likely Pathogenic/Pathogenic. The c.4021C>T variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.4021C>T variant in FLNC is located in exon 23 of this 48-exon gene, predicted to incorporate a premature termination codon (p.(Arg1341Ter)), and is expected to result in loss-of-function via nonsense mediated decay. Multiple loss-of-function variants that are downstream to the c.4021C>T variant have been reported in the literature [PMID:32112656] and ClinVar [ClinVar ID: 620418, 620286, others] in individuals with FLNC-related conditions. Based on available evidence this c.4021C>Tp.(Arg1341Ter) variant identified in FLNC is classified as Likely Pathogenic. (less)
Observation 1:
Clinical Features:
Cardiomyopathy (present)
Secondary finding: yes
Observation 2:
Clinical Features:
Atrial fibrillation (present)
Secondary finding: yes
|
|
Pathogenic
(Mar 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Distal myopathy with posterior leg and anterior hand involvement
Dilated Cardiomyopathy, Dominant Myofibrillar myopathy 5 Hypertrophic cardiomyopathy 26
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001232819.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry … (more)
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 620373). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. This sequence change creates a premature translational stop signal (p.Arg1341*) in the FLNC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349). (less)
|
|
Pathogenic
(Jan 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
FLNC-related disorders
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004801409.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The FLNC c.4021C>T p.(Arg1341Ter) nonsense variant results in the substitution of arginine at amino acid position 1341 with a stop codon. This variant disrupts exon … (more)
The FLNC c.4021C>T p.(Arg1341Ter) nonsense variant results in the substitution of arginine at amino acid position 1341 with a stop codon. This variant disrupts exon 23 of 48 on the canonical transcript and loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in a heterozygous state in one individual with dilated cardiomyopathy (Burstein et al. 2020). Additionally, several disease-causing variants located downstream of the p.Arg1341Ter variant are reported in the peer-reviewed literature and ClinVar database (Ortiz-Genga et al. 2016; Landrum et al. 2018). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.4021C>T p.(Arg1341Ter) variant is classified as pathogenic for FLNC-related disorders. (less)
|
|
Likely pathogenic
(Jul 21, 2023)
|
no assertion criteria provided
Method: research
|
Hypertrophic cardiomyopathy 26
Affected status: yes
Allele origin:
germline
|
deCODE genetics, Amgen
Accession: SCV004022148.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_001458.5:c.4021C>T (chr7:128846357) in FLNC was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar … (more)
The variant NM_001458.5:c.4021C>T (chr7:128846357) in FLNC was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. (less)
Number of individuals with the variant: 1
Ethnicity/Population group: Icelandic
|
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 |
---|---|---|---|---|
Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies. | Ortiz-Genga MF | Journal of the American College of Cardiology | 2016 | PMID: 27908349 |
Text-mined citations for rs1562998062 ...
HelpRecord last updated Apr 20, 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.