Submissions for variant NM_001110556.2(FLNA):c.1571G>A (p.Gly524Glu)

dbSNP: rs1557178957

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001865666	SCV002109986	uncertain significance	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2022-11-08	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with heterotaxy syndrome (PMID: 32738303). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FLNA protein function. ClinVar contains an entry for this variant (Variation ID: 440936). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 524 of the FLNA protein (p.Gly524Glu).
GeneDx	RCV002254928	SCV002526169	uncertain significance	not provided	2022-06-09	criteria provided, single submitter	clinical testing	Reported in a patient with heterotaxy syndrome, but segregation and detailed clinical information are not provided (Liang et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25686753, 32078439, 32738303)
GenomeConnect, ClinGen	RCV000509147	SCV000606882	not provided	Cardiac valvular dysplasia, X-linked; FG syndrome 2; Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type I; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia 1		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.