Submissions for variant NM_001291303.3(FAT4):c.8021A>T (p.Asp2674Val)

gnomAD frequency: 0.00121  dbSNP: rs138655269

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481182	SCV000569120	uncertain significance	not provided	2018-05-14	criteria provided, single submitter	clinical testing	The D2672V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D2672V variant is observed in 315/126102 (0.25%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The D2672V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. GeneDx interprets D2672V as a variant of uncertain significance.
Undiagnosed Diseases Network, NIH	RCV000626046	SCV000746665	uncertain significance	Van Maldergem syndrome 2	2016-11-16	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000626046	SCV001571471	uncertain significance	Van Maldergem syndrome 2	2021-03-01	criteria provided, single submitter	research	The FAT4 c.8015A>T (p.Asp2672Val) missense variant is located in exon 10, and results in a single amino acid substitution from an aspartic acid to a valine. This variant was detected in the compound heterozygous state in an individual with Van Maldergem syndrome 2; this individual was also reported to have diploid/triploid mosaicism (ClinVar entry from Undiagnosed Diseases Network). The variant was also described in the homozygous state in a 3 year-old male with suspected Van Maldergem syndrome; he also had compound heterozygous variants in CYP21A2 and was diagnosed with congenital adrenal hyperplasia (PMID: 31384091). FAT4 c.8015A>T (p.Asp2672Val) is present in human population databases (allele frequency 383 alleles/281150 total alleles: 0.001). Due to the limited information regarding this variant, it is classified as a VUS.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000481182	SCV001657028	likely benign	not provided	2025-01-29	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000481182	SCV002011011	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000481182	SCV004564688	uncertain significance	not provided	2023-10-26	criteria provided, single submitter	clinical testing	The FAT4 c.8015A>T; p.Asp2672Val variant (rs138655269), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 420323). This variant is found in the non-Finnish European population with an overall allele frequency of 0.25% (324/128362 alleles) in the Genome Aggregation Database. The aspartate at codon 2672 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.396). Due to limited information, the clinical significance of the p.Asp2672Val variant is uncertain at this time.
Daryl Scott Lab, Baylor College of Medicine	RCV003972810	SCV005871012	uncertain significance	FAT4-related disorder	2024-01-01	criteria provided, single submitter	clinical testing	PM3, PP3
PreventionGenetics, part of Exact Sciences	RCV003972810	SCV004790951	likely benign	FAT4-related disorder	2022-09-02	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).