rs782434042

Description

The FLNA c.1462C>T; p.Arg488Trp variant (rs782434042), to our knowledge, is not reported in the medical literature or in gene-specific databases, but is observed in the general population at a low overall frequency of 0.0016% (3/177959, 1 hemizygote) in the Genome Aggregation Database. The arginine at codon 488 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty. Pathogenic variants in FLNA are causative for a number of X-linked disorders: (1) Otopalatodigital Spectrum Disorders: frontometaphyseal dysplasia (MIM:305620), Melnick-Needles syndrome (MIM:309350), otopalatodigital syndrome, type I (MIM:311300), otopalatodigital syndrome, type II (MIM:304120), terminal osseous dysplasia (MIM:300244); (2) periventricular heterotopia (MIM:300049; mostly affects females, as males have early lethality); (3) intestinal pseudoobstruction, neuronal (MIM: 300048) or congenital short bowel syndrome (MIM:300048); and (4) X-linked cardiac valvular dysplasia (MIM:314400; X-CVD) has been reported in six unrelated pedigrees, three of whom had missense variants and three of whom had the same large deletion predicted to yield an in-frame mRNA (Kyndt 2007). In the families reported, penetrance was complete in males, but incomplete with variable expressivity in females. Overall, the clinical presentation for the same FLNA gene variant in males is usually more severe than females, who benefit from random X-inactivation. Kyndt F et al. Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy. Circulation. 2007 Jan 2;115(1):40-9.