Submissions for variant NM_001110556.2(FLNA):c.5251C>T (p.Pro1751Ser)

gnomAD frequency: 0.00069  dbSNP: rs56102764

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000473909	SCV000250347	benign	not provided	2019-05-22	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000196068	SCV000297013	benign	not specified	2015-10-20	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000196068	SCV000331587	benign	not specified	2016-09-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084884	SCV000556049	likely benign	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2024-01-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000196068	SCV000594796	likely benign	not specified	2016-03-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020363	SCV000738383	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-01-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000680536	SCV000807945	likely benign	Connective tissue disorder	2018-06-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000473909	SCV001150527	uncertain significance	not provided	2016-05-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000196068	SCV001475120	benign	not specified	2020-08-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000473909	SCV002048947	benign	not provided	2022-06-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196068	SCV004039151	likely benign	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: FLNA c.5251C>T (p.Pro1751Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 166980 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes and 24 hemizygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3200 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 Non-Finnish European origin. To our knowledge, no occurrence of c.5251C>T in individuals affected with Periventricular Nodular Heterotopia and no experimental evidence demonstrating its impact on protein function have been reported. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=9) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000473909	SCV001744767	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000473909	SCV001798685	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000473909	SCV001927416	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000473909	SCV001968943	likely benign	not provided		no assertion criteria provided	clinical testing