Submissions for variant NM_001458.5(FLNC):c.1519G>A (p.Gly507Arg)

gnomAD frequency: 0.00060  dbSNP: rs189525930

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727134	SCV000565015	benign	not provided	2019-08-26	criteria provided, single submitter	clinical testing	Has not been previously published in association with FLNC-related disorders to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 418215; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26555887)
Invitae	RCV001084196	SCV000650907	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727134	SCV000706047	uncertain significance	not provided	2017-02-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727134	SCV002506084	likely benign	not provided	2023-08-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002395142	SCV002705286	benign	Cardiovascular phenotype	2021-06-23	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150234	SCV003837892	benign	Cardiomyopathy	2021-12-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000727134	SCV004224103	uncertain significance	not provided	2022-02-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000727134	SCV004701401	benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	FLNC: PP3, BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525941	SCV005040383	likely benign	not specified	2024-03-31	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.1519G>A (p.Gly507Arg) results in a non-conservative amino acid change located in the third immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 1607036 control chromosomes, predominantly at a frequency of 0.0054 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1519G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported (MYBPC3 c.2308G>A, p.Asp770Asn; TTR c.424G>A, p.Val142Ile), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. ClinVar contains an entry for this variant (Variation ID: 42543). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000727134	SCV001923554	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000727134	SCV001929972	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000727134	SCV001954219	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000727134	SCV001973555	likely benign	not provided		no assertion criteria provided	clinical testing