Submissions for variant NM_001110556.2(FLNA):c.6372C>G (p.His2124Gln)

dbSNP: rs781999359

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001332005	SCV001524188	uncertain significance	Oto-palato-digital syndrome, type I	2019-12-11	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002368112	SCV002657297	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-07-13	criteria provided, single submitter	clinical testing	The p.H2116Q variant (also known as c.6348C>G), located in coding exon 37 of the FLNA gene, results from a C to G substitution at nucleotide position 6348. The histidine at codon 2116 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002546522	SCV003461913	uncertain significance	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2022-08-17	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 1030454). This missense change has been observed in individual(s) with prune belly syndrome (PMID: 30143558). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2116 of the FLNA protein (p.His2116Gln).
Revvity Omics, Revvity	RCV003145577	SCV003832727	uncertain significance	not provided	2021-04-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230663	SCV003929220	uncertain significance	not specified	2023-04-05	criteria provided, single submitter	clinical testing	Variant summary: FLNA c.6348C>G (p.His2116Gln) results in a non-conservative amino acid change located in the Filamin repeat 19 (IPR001298) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 181432 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6348C>G has been reported in the literature in at least one hemizygous individual, who was affected with prune belly syndrome and congenital anomalies of the kidney and urinary tract, however, without strong evidence for causality (van der Ven_2018). This report does not provide unequivocal conclusions about association of the variant with Periventricular Nodular Heterotopia 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.