Submissions for variant NM_001458.5(FLNC):c.7560C>T (p.Thr2520=)

gnomAD frequency: 0.00004  dbSNP: rs527921534

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000547791	SCV000651170	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change affects codon 2520 of the FLNC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FLNC protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs527921534, gnomAD 0.02%). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 472177). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000786412	SCV002063156	likely benign	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003159900	SCV003856288	likely benign	Cardiovascular phenotype	2022-12-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000786412	SCV004237835	likely benign	not provided	2023-10-20	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786412	SCV000925230	uncertain significance	not provided	2017-09-11	no assertion criteria provided	provider interpretation	c.7560C>T (silent, splice region) in exon 45 of the FLNC gene (NM_001458.4; chr7-128496974-C-T) SCICD classification: variant of uncertain significance based on lack of case data. However, this variant is relatively prevalent in some ethnic populations. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: Both missense and truncating variants in FLNC have been reported in various cardiomyopathies (Ortiz-Genga et al. 2016; Valdes-Mas et al 2014). Variant type: Missense. Case data: · ClinVar: not present · Cases in the literature: none reported Functional data: none reported. In silico models (for missense variants only): not applicable Splicing algorithms: Per the test report, "Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies." Conservation data: The thymine at position 7560 in the cDNA is completely conserved across species, as are neighboring nucleotides. Other variants associated with disease at this nucleotide: none Population data: MAF=0.02% in East Asians: · The variant was reported online in 8 of 137,599 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 4 of 9,414 individuals of East Asian descent (MAF=0.02%), 3 of 15,367 individuals of South Asian descent and 1 of 62,589 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.