Submissions for variant NM_003977.4(AIP):c.301G>A (p.Val101Met)

gnomAD frequency: 0.00085  dbSNP: rs147931650

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000272200	SCV000373576	benign	Somatotroph adenoma	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.
Ambry Genetics	RCV000567882	SCV000672432	likely benign	Hereditary cancer-predisposing syndrome	2020-03-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Invitae	RCV001441310	SCV001644237	likely benign	not provided	2024-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001441310	SCV002039032	uncertain significance	not provided	2021-08-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27535533)
Sema4, Sema4	RCV000567882	SCV002535437	likely benign	Hereditary cancer-predisposing syndrome	2020-10-23	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003967877	SCV004780455	likely benign	AIP-related disorder	2022-06-28	criteria provided, single submitter	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).
Genetic Services Laboratory, University of Chicago	RCV003151020	SCV003839404	uncertain significance	not specified	2022-06-20	no assertion criteria provided	clinical testing	DNA sequence analysis of the AIP gene demonstrated a sequence change, c.301G>A, in exon 3 that results in an amino acid change, p.Val101Met. This sequence change does not appear to have been previously described in individuals with AIP-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.25% in the African subpopulation (dbSNP rs147931650). The p.Val101Met change affects a highly conserved amino acid residue located in a domain of the AIP protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val101Met substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val101Met change remains unknown at this time.