Submissions for variant NM_003977.4(AIP):c.517G>A (p.Glu173Lys)

gnomAD frequency: 0.00034  dbSNP: rs138902236

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000294654	SCV000373579	benign	Somatotroph adenoma	2018-01-12	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.
Ambry Genetics	RCV000567733	SCV000672429	benign	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000733441	SCV000861511	uncertain significance	not provided	2018-06-07	criteria provided, single submitter	clinical testing
Invitae	RCV000733441	SCV001598069	likely benign	not provided	2024-01-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000733441	SCV002588020	uncertain significance	not provided	2022-04-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003409472	SCV004113235	uncertain significance	AIP-related disorder	2023-12-19	criteria provided, single submitter	clinical testing	The AIP c.517G>A variant is predicted to result in the amino acid substitution p.Glu173Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD, which is more common than expected for a primary cause of disease. In ClinVar, this variant has conflicting interpretations ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/305729/). Although we suspect this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.