Submissions for variant NM_001291303.3(FAT4):c.14756T>C (p.Leu4919Pro)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002993850	SCV003291884	uncertain significance	not provided	2022-06-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 4917 of the FAT4 protein (p.Leu4917Pro). This variant is present in population databases (rs140963523, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with FAT4-related conditions. 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 FAT4 protein function. 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.
Ambry Genetics	RCV004978433	SCV005579851	uncertain significance	Inborn genetic diseases	2024-08-20	criteria provided, single submitter	clinical testing	The c.14750T>C (p.L4917P) alteration is located in exon 17 (coding exon 17) of the FAT4 gene. This alteration results from a T to C substitution at nucleotide position 14750, causing the leucine (L) at amino acid position 4917 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005051994	SCV005685360	uncertain significance	Hennekam lymphangiectasia-lymphedema syndrome 2	2024-07-19	criteria provided, single submitter	clinical testing	A FAT4 c.14756T>C (p.Leu4919Pro) variant was identified at a near heterozygous allelic fraction of 46.4%, a frequency which may be consistent with it being of germline origin. This variant, to our knowledge, has not been reported in the medical literature. It is only observed on 121/1,614,054 alleles in the general population (gnomAD v.4.1.0), indicating that it is not a common variant. This variant has been reported in the ClinVar database as a germline variant of uncertain significance by one submitter (ClinVar ID: 2078592). Computational predictors are uncertain as to the impact of this variant on FAT4 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the FAT4 c.14756T>C (p.Leu4919Pro) variant is uncertain at this time.