Submissions for variant NM_001110556.2(FLNA):c.1864G>A (p.Glu622Lys)

dbSNP: rs1131691935

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494059	SCV000583175	likely pathogenic	not provided	2015-09-05	criteria provided, single submitter	clinical testing	The E622K variant in the FLNA gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The E622K variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E622K variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The E622K variant is a strong candidate for a disease-causing variant, which may be related to the clinical features reported in this individual. However, the possibility that E622K may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865554	SCV002190871	uncertain significance	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 622 of the FLNA protein (p.Glu622Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 430383). 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 with a negative predictive value of 95%. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000494059	SCV005042339	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	FLNA: PM2, PP3