ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.4108C>T (p.Arg1370Ter)

dbSNP: rs1342121466
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001044407 SCV001208203 pathogenic Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2024-01-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1370*) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 842060). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002272394 SCV002557319 pathogenic Hypertrophic cardiomyopathy 26 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with FLNC-related disease. Loss of function variants have been reported to cause myopathy, myofibrillar, 5 (MIM#609524), myopathy, distal, 4 (MIM#614065), familial hypertrophic cardiomyopathy, 26 (MIM#617047) and dilated cardiomyopathy. Gain of function variants have also been reported to cause myopathy, distal, 4 (MIM#614065) (PMID: 28008423, PMID: 23109048). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported as pathogenic, and have been observed many in patients with dilated cardiomyopathy, and less commonly with arrhythmogenic cardiomyopathy or distal myopathy (ClinVar, PMID: 32112656). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in a deceased patient with arrhythmogenic cardiomyopathy (ClinVar, PMID: 31627847). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
DASA RCV002272394 SCV002588795 pathogenic Hypertrophic cardiomyopathy 26 2022-11-03 criteria provided, single submitter clinical testing The c.4108C>T;p.(Arg1370*) variant creates a premature translational stop signal in the FLNC gene. It is expected to result in an absent or disrupted protein product - PVS1. ClinVar contains an entry for this variant (ClinVar ID: 842060) - PS4_supporting. This variant is not present in population databases (rs1342121466, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.
Ambry Genetics RCV002320257 SCV002631465 pathogenic Cardiovascular phenotype 2020-11-04 criteria provided, single submitter clinical testing The p.R1370* pathogenic mutation (also known as c.4108C>T), located in coding exon 23 of the FLNC gene, results from a C to T substitution at nucleotide position 4108. 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.

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