Submissions for variant NM_001458.5(FLNC):c.2278G>A (p.Glu760Lys)

gnomAD frequency: 0.00001  dbSNP: rs772574007

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000649182	SCV000771007	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-08-30	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470941	SCV002769462	uncertain significance	Hypertrophic cardiomyopathy 26	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is the established mechanism of disease for variants in dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy (MIM#617047) and myofibrillar myopathy (MIM#609524), and recently has been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC; PMID: 31627847). In distal myopathy (MIM#614065), NMD-predicted variants cause a loss of function, however missense variants have been shown to result in a toxic gain of function (PMID: 32112656). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In four families with ARVC associated with FLNC variants, majority of variant carriers had ECG repolarisation and depolarisation abnormalities, which in isolation, are not considered diagnostic criteria for ARVC, and had no detectable echocardiographic disease features (PMID: 31627847). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0806 - This variant has moderate previous evidence of being benign in unrelated individuals. It has been reported as a VUS by a clinical testing laboratory (ClinVar). However, they recently re-classified this variant as likely benign, as it has been identified in three affected individuals who each had a genetic diagnosis in a different gene and an unaffected individual (personal communication). (SB) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV003144444	SCV003833095	uncertain significance	not provided	2019-02-05	criteria provided, single submitter	clinical testing