Submissions for variant NM_001458.5(FLNC):c.1166G>A (p.Gly389Asp)

gnomAD frequency: 0.00016  dbSNP: rs763039506

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487193	SCV000565014	benign	not provided	2022-07-13	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Invitae	RCV000649173	SCV000770998	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002475928	SCV002784606	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2021-09-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150233	SCV003837889	uncertain significance	Cardiomyopathy	2022-03-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401513	SCV004122459	likely benign	not specified	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: FLNC c.1166G>A (p.Gly389Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 249496 control chromosomes. The observed variant frequency is approximately 14 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. To our knowledge, no occurrence of c.1166G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV004023106	SCV005017666	likely benign	Cardiovascular phenotype	2023-11-17	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000487193	SCV001739723	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000487193	SCV001929540	uncertain significance	not provided		no assertion criteria provided	clinical testing