Submissions for variant NM_001110556.2(FLNA):c.6635_6638del (p.Val2212fs)

dbSNP: rs786205178

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Claritas Genomics	RCV000170398	SCV000222820	pathogenic	Heterotopia, periventricular, X-linked dominant	2010-10-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000199583	SCV000250415	pathogenic	not provided	2015-06-08	criteria provided, single submitter	clinical testing	The c.6611_6614delTCAG ( or c.6635delTCAG due to use of alternate transcript) mutation in the FLNA gene has previously been reported in association with FLNA-disorder in a 42-year-old female with ventricular septal defects and aortic regurgitation, surgically corrected ventricular septal defect, bilateral PH and enlarged retrocerebellar space (de Wit MC et al., 2011). This individuals family history revealed her mother died of rupture of aorta, sibling with mild aortic regurgitation, and the patient had a healthy son (De Wit et al., 2011). This mutation causes a shift in reading frame starting at codon Valine 2204, changing it to an Alanine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Val2204AlafsX2. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the FLNA gene have been reported in association with FLNA-related disorder. Furthermore, the c.6611_6614delTCAG mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.6611_6614delTCAG in the FLNA gene is interpreted as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV000199583	SCV004033338	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	FLNA: PVS1, PM2, PS4:Supporting
Invitae	RCV003765061	SCV004571473	pathogenic	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2022-11-12	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: 190179). This premature translational stop signal has been observed in individual(s) with periventricular heterotopia (PMID: 20730588). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val2204Alafs*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).