Submissions for variant NM_001458.5(FLNC):c.5278G>A (p.Gly1760Ser)

gnomAD frequency: 0.00002  dbSNP: rs150986092

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000525434	SCV000651068	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1760 of the FLNC protein (p.Gly1760Ser). This variant is present in population databases (rs150986092, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with FLNC-related conditions (PMID: 28403181, 30411535, 30418145, 33250842). ClinVar contains an entry for this variant (Variation ID: 472098). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001312149	SCV001763987	uncertain significance	not provided	2020-05-07	criteria provided, single submitter	clinical testing	Reported in a patient with limb-girdle muscular dystrophy and a patient with HCM (Yu et al., 2017; Cui et al., 2018); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 472098; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30411535, 28403181)
Ambry Genetics	RCV002350343	SCV002642639	likely benign	Cardiovascular phenotype	2019-12-23	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.
Fulgent Genetics, Fulgent Genetics	RCV002491080	SCV002789553	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2021-08-20	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001312149	SCV001917037	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001312149	SCV001976183	uncertain significance	not provided		no assertion criteria provided	clinical testing