Submissions for variant NM_001110556.2(FLNA):c.1133_1134del (p.Gln378fs)

dbSNP: rs1603362871

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008230	SCV001167996	likely pathogenic	not provided	2018-07-03	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the FLNA gene. The c.1133_1134delAG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1133_1134delAG variant is not observed in large population cohorts (Lek et al., 2016). The c.1133_1134delAG variant causes a frameshift starting with codon Glutamine 378, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Gln378ArgfsX2. This likely pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003769410	SCV004596602	pathogenic	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2023-04-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817127). This variant has not been reported in the literature in individuals affected with FLNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln378Argfs*2) in the FLNA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLNA are known to be pathogenic (PMID: 16684786, 20730588, 26471271).