Submissions for variant NM_001458.5(FLNC):c.1965_1966del (p.Ala656fs)

dbSNP: rs1585156450

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008981	SCV001168789	likely pathogenic	not provided	2018-08-09	criteria provided, single submitter	clinical testing	Although the c.1965_1966delTG likely pathogenic variant in the FLNC gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon alanine 656, changing it to a proline, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Ala656ProfsX8. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other downstream frameshift variants in the FLNC gene have been reported in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.1965_1966delTG variant has not been observed in large population cohorts (Lek et al., 2016).In summary, c.1965_1966delTG in the FLNC gene is interpreted as a likely pathogenic variant.
Invitae	RCV001388841	SCV001589991	pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2020-02-24	criteria provided, single submitter	clinical testing	Loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with FLNC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ala656Profs*8) in the FLNC gene. It is expected to result in an absent or disrupted protein product.