Submissions for variant NM_000043.6(FAS):c.578A>G (p.Lys193Arg)

gnomAD frequency: 0.00026  dbSNP: rs150489856

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625369	SCV000745108	likely benign	Autoimmune lymphoproliferative syndrome type 1	2017-06-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658571	SCV000780348	uncertain significance	not provided	2018-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625369	SCV001264920	benign	Autoimmune lymphoproliferative syndrome type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000625369	SCV001567629	uncertain significance	Autoimmune lymphoproliferative syndrome type 1	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 193 of the FAS protein (p.Lys193Arg). This variant is present in population databases (rs150489856, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 522316). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FAS 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.
GeneDx	RCV000658571	SCV002032489	uncertain significance	not provided	2023-10-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000625369	SCV003924106	likely benign	Autoimmune lymphoproliferative syndrome type 1	2021-03-30	criteria provided, single submitter	clinical testing	FAS NM_000043.5 exon 7 p.Lys193Arg (c.578A>G): This variant has not been reported in the literature but is present in 0.1% (16/15288) of Latino alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/10-89012008-A-G?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Benign (Variation ID:522316). Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625369	SCV000745798	likely benign	Autoimmune lymphoproliferative syndrome type 1	2016-01-24	no assertion criteria provided	clinical testing