Submissions for variant NM_005245.4(FAT1):c.7130C>T (p.Thr2377Met)

gnomAD frequency: 0.00071  dbSNP: rs201363601

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001356956	SCV003280648	likely benign	not provided	2024-01-03	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356956	SCV001552260	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FAT1 p.Thr2377Met variant was not identified in the literature nor was it identified in ClinVar or Cosmic. The variant was identified in dbSNP (ID: rs201363601) and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 175 of 266066 chromosomes at a frequency of 0.0006577 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: East Asian in 38 of 18830 chromosomes (freq: 0.002018), Other in 8 of 6612 chromosomes (freq: 0.00121), European (non-Finnish) in 94 of 117390 chromosomes (freq: 0.000801), Latino in 14 of 35036 chromosomes (freq: 0.0004), European (Finnish) in 9 of 25006 chromosomes (freq: 0.00036), African in 6 of 22834 chromosomes (freq: 0.000263) and South Asian in 6 of 30506 chromosomes (freq: 0.000197), but was not observed in the Ashkenazi Jewish population. The p.Thr2377 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
O&I group, Department of Genetics, University Medical Center of Groningen	RCV001849190	SCV001960873	uncertain significance	Autosomal dominant cerebellar ataxia	2021-07-22	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004548203	SCV004729395	likely benign	FAT1-related disorder	2023-06-07	no assertion criteria provided	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).