Submissions for variant NM_001110556.2(FLNA):c.2449C>T (p.Pro817Ser)

gnomAD frequency: 0.00029  dbSNP: rs200053635

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000198787	SCV000226598	likely benign	not specified	2016-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000416150	SCV000250377	likely benign	not provided	2020-09-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000416150	SCV000493506	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000416150	SCV000511493	likely benign	not provided	2016-09-20	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000416150	SCV000603745	benign	not provided	2021-10-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087877	SCV000639771	benign	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2024-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002313039	SCV000739061	benign	Familial thoracic aortic aneurysm and aortic dissection	2017-06-22	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000680542	SCV000807952	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000198787	SCV004122455	benign	not specified	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: FLNA c.2449C>T (p.Pro817Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 180748 control chromosomes, predominantly at a frequency of 0.00079 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2528 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNA causing Periventricular Nodular Heterotopia phenotype (3.1e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2449C>T has been reported in the literature in individuals affected with various diseases such as disorders of gonadal development, congenital macrothrombocytopenia and connective tissue disorders, without strong evidence for causality (examples, Renner_2019, Zidoune_2022, Smolag_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Periventricular Nodular Heterotopia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30675029, 34858435, 36110220). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Benign/Likely benign, n=7; VUS, n=2). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000509326	SCV004783972	likely benign	FLNA-related disorder	2019-09-24	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
GenomeConnect, ClinGen	RCV000509326	SCV000606946	not provided	FLNA-related disorder		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Human Developmental Genetics, Institut Pasteur	RCV001568328	SCV001786690	uncertain significance	Disorder of sexual differentiation	2021-08-15	no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000416150	SCV001977812	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000416150	SCV001979775	likely benign	not provided		no assertion criteria provided	clinical testing