Submissions for variant NM_001110556.2(FLNA):c.6728C>G (p.Ala2243Gly)

gnomAD frequency: 0.00002  dbSNP: rs953454766

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640755	SCV000762354	likely benign	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2025-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001756067	SCV001987885	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Ambry Genetics	RCV004025609	SCV003583069	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-27	criteria provided, single submitter	clinical testing	The p.A2235G variant (also known as c.6704C>G), located in coding exon 39 of the FLNA gene, results from a C to G substitution at nucleotide position 6704. The alanine at codon 2235 is replaced by glycine, an amino acid with similar properties. Based on data from gnomAD, the G allele has an overall frequency of 0.0028% (5/178508) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0050% (4/79320) of European (non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387899	SCV004099987	uncertain significance	not specified	2023-09-19	criteria provided, single submitter	clinical testing	Variant summary: FLNA c.6728C>G (p.Ala2243Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 178508 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6728C>G in individuals affected with Periventricular Nodular Heterotopia 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788070	SCV005398576	uncertain significance	Cardiac valvular dysplasia, X-linked	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Cardiac valvular dysplasia is caused by loss-of-function (PMID: 30089473). (N) 0109 - This gene is known to be associated with X-linked dominant and recessive disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glycine (exon 41). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 (5 heterozygotes, 1 hemizygote, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (filamin-type immunoglobulin domain; NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are inconclusive. This variant has been reported as a VUS (ClinVar). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Mayo Clinic Laboratories, Mayo Clinic	RCV001756067	SCV005411495	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	PP2, PP3, PM2