Submissions for variant NM_001447.3(FAT2):c.5629T>C (p.Tyr1877His)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002953953	SCV003281047	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1877 of the FAT2 protein (p.Tyr1877His). This variant is present in population databases (rs144352685, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with FAT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2067437). 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 expected to disrupt FAT2 protein function with a positive 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.
CeGaT Center for Human Genetics Tuebingen	RCV002953953	SCV004032638	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	FAT2: BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331408	SCV004038757	uncertain significance	not specified	2023-08-21	criteria provided, single submitter	clinical testing	Variant summary: FAT2 c.5629T>C (p.Tyr1877His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251068 control chromosomes (i.e., 45 heterozygotes; gnomAD v2.1 Exomes dataset). Although the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, these data suggest that the variant might not be associated with high-penetrance, early-onset, dominant disease. To our knowledge, no occurrence of c.5629T>C in individuals affected with Spinocerebellar Ataxia 45 and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV003331408	SCV004869972	uncertain significance	not specified	2023-10-13	criteria provided, single submitter	clinical testing	The c.5629T>C (p.Y1877H) alteration is located in exon 9 (coding exon 9) of the FAT2 gene. This alteration results from a T to C substitution at nucleotide position 5629, causing the tyrosine (Y) at amino acid position 1877 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.