Submissions for variant NM_001458.5(FLNC):c.4022G>A (p.Arg1341Gln)

gnomAD frequency: 0.00068  dbSNP: rs149641783

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724874	SCV000228031	uncertain significance	not provided	2015-06-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000724874	SCV000513071	benign	not provided	2020-01-10	criteria provided, single submitter	clinical testing
Invitae	RCV001084885	SCV000651013	benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724874	SCV002545559	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	FLNC: BS1
Ambry Genetics	RCV002354450	SCV002622342	likely benign	Cardiovascular phenotype	2019-01-09	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150047	SCV003837898	benign	Cardiomyopathy	2021-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001706129	SCV004122458	likely benign	not specified	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: FLNC c.4022G>A (p.Arg1341Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 248756 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 133.79 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Dilated Cardiomyopathy phenotype (7.8e-06), strongly suggesting that the variant is benign. c.4022G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy, without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28356264, 25208129). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as VUS whle five classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003907585	SCV004727308	benign	FLNC-related disorder	2020-03-11	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Clinical Genetics, Academic Medical Center	RCV001706129	SCV001919732	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000724874	SCV001929608	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724874	SCV001970442	likely benign	not provided		no assertion criteria provided	clinical testing