ClinVar Miner

Submissions for variant NM_001110556.2(FLNA):c.901C>T (p.Arg301Trp) (rs192609440)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723962 SCV000231624 uncertain significance not provided 2014-08-13 criteria provided, single submitter clinical testing
GeneDx RCV000723962 SCV000279720 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing The R301W variant of uncertain significance in the FLNA gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 12/198654 (0.006%) alleles from individuals of multiple ethnic backgrounds, including multiple unrelated hemizygous individuals in large population cohorts and undergoing testing at GeneDx, which is greater than expected for this disorder (Lek et al., 2016). However, the R301W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000471973 SCV000543675 uncertain significance Periventricular nodular heterotopia 1; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia 2019-09-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 301 of the FLNA protein (p.Arg301Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs192609440, ExAC 0.01%). This variant has not been reported in the literature in individuals with a FLNA-related disease. ClinVar contains an entry for this variant (Variation ID: 198133). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Genetic Services Laboratory, University of Chicago RCV000221578 SCV000594822 uncertain significance not specified 2016-10-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764865 SCV000896021 uncertain significance Cardiac valvular dysplasia, X-linked; FG syndrome 2; Periventricular nodular heterotopia 1; Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked; Melnick-Needles syndrome; Oto-palato-digital syndrome, type I; Oto-palato-digital syndrome, type II; Terminal osseous dysplasia; Frontometaphyseal dysplasia 1 2018-10-31 criteria provided, single submitter clinical testing

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