Submissions for variant NM_001458.5(FLNC):c.470G>A (p.Arg157His)

gnomAD frequency: 0.00001  dbSNP: rs752919962

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000817620	SCV000958189	likely benign	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
Ambry Genetics	RCV002336694	SCV002637940	uncertain significance	Cardiovascular phenotype	2022-11-20	criteria provided, single submitter	clinical testing	The p.R157H variant (also known as c.470G>A), located in coding exon 2 of the FLNC gene, results from a G to A substitution at nucleotide position 470. The arginine at codon 157 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470992	SCV002769065	uncertain significance	Hypertrophic cardiomyopathy 26	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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). 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 (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (15 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 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. However two alternative changes, p.(Arg157Cys) and p.(Arg157Gly), with stronger Grantham score have been reported as VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS (ClinVar). (I) 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
Fulgent Genetics, Fulgent Genetics	RCV002501127	SCV002814965	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2021-07-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003145194	SCV003833077	uncertain significance	not provided	2021-08-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003145194	SCV004161023	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing