Submissions for variant NM_001458.5(FLNC):c.2128G>A (p.Asp710Asn)

gnomAD frequency: 0.00020  dbSNP: rs370035829

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556556	SCV000650933	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2025-01-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002420499	SCV002728987	likely benign	Cardiovascular phenotype	2021-07-28	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.
Revvity Omics, Revvity	RCV003144349	SCV003833207	uncertain significance	not provided	2023-02-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486874	SCV004240626	likely benign	Cardiomyopathy	2023-02-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056158	SCV005726707	likely benign	not specified	2024-11-18	criteria provided, single submitter	clinical testing	Variant summary: FLNC c.2128G>A (p.Asp710Asn) results in a conservative amino acid change located in the Filamin/ABP280 repeat-like domain (IPR017868) of 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 0.00032 in 248492 control chromosomes, predominantly at a frequency of 0.00087 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 111-fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Dilated Cardiomyopathy phenotype (7.8e-06). c.2128G>A has been reported in the literature (example: Jensson_2023) without strong evidence for or against pathogenicity. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37937776). ClinVar contains an entry for this variant (Variation ID: 471997). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003962560	SCV004792062	likely benign	FLNC-related disorder	2023-03-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).