ClinVar Miner

Submissions for variant NM_001291303.3(FAT4):c.821C>T (p.Ala274Val)

gnomAD frequency: 0.00009  dbSNP: rs199605036
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001946071 SCV002215217 uncertain significance not provided 2024-03-20 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 274 of the FAT4 protein (p.Ala274Val). This variant is present in population databases (rs199605036, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FAT4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1433546). 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 with a negative predictive value of 80%. 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 RCV003247194 SCV003939973 uncertain significance Inborn genetic diseases 2023-06-06 criteria provided, single submitter clinical testing The c.821C>T (p.A274V) alteration is located in exon 1 (coding exon 1) of the FAT4 gene. This alteration results from a C to T substitution at nucleotide position 821, causing the alanine (A) at amino acid position 274 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genomics Laboratory, Washington University in St. Louis RCV004558745 SCV005047092 uncertain significance Hennekam lymphangiectasia-lymphedema syndrome 2 2024-01-08 criteria provided, single submitter clinical testing A FAT4 c.821C>T (p. Ala274Val) variant was identified at a near heterozygous allelic fraction of 48.6%, a frequency consistent with germline origin. This variant, to our knowledge, has not been reported in the medical literature in relation to FAT4-related disease. It has been reported in the ClinVar database as a germline variant of uncertain significance by two submitters (ClinVar ID: 1433546). The FAT4 c.821C>T (p. Ala274Val) variant is observed on 137/1,579,040 alleles in the general population (gnomAD v.4.0.0). 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 this variant is uncertain at this time.
Fulgent Genetics, Fulgent Genetics RCV005031930 SCV005664918 uncertain significance Van Maldergem syndrome 2; Hennekam lymphangiectasia-lymphedema syndrome 2 2024-05-16 criteria provided, single submitter clinical testing

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