Submissions for variant NM_003659.4(AGPS):c.214A>G (p.Thr72Ala)

gnomAD frequency: 0.00031  dbSNP: rs560217758

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202921	SCV000257941	uncertain significance	not specified	2015-06-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000764289	SCV000419562	uncertain significance	Rhizomelic chondrodysplasia punctata type 3	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Eurofins Ntd Llc (ga)	RCV000676026	SCV000704479	uncertain significance	not provided	2017-01-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764289	SCV000895308	uncertain significance	Rhizomelic chondrodysplasia punctata type 3	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000676026	SCV003245321	uncertain significance	not provided	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 72 of the AGPS protein (p.Thr72Ala). This variant is present in population databases (rs560217758, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with AGPS-related conditions. ClinVar contains an entry for this variant (Variation ID: 218623). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Ambry Genetics	RCV002515498	SCV003538097	uncertain significance	Inborn genetic diseases	2022-08-19	criteria provided, single submitter	clinical testing	The c.214A>G (p.T72A) alteration is located in exon 1 (coding exon 1) of the AGPS gene. This alteration results from a A to G substitution at nucleotide position 214, causing the threonine (T) at amino acid position 72 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD) database, the AGPS c.214A>G alteration was observed in 0.03% (49/177946) of total alleles studied, with a frequency of 0.13% (7/5340) in the Other subpopulation. This amino acid position is well conserved in available vertebrate species. The p.T72A alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000764289	SCV004563406	uncertain significance	Rhizomelic chondrodysplasia punctata type 3	2023-09-11	criteria provided, single submitter	clinical testing	The AGPS c.214A>G; p.Thr72Ala variant (rs560217758), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 218623). This variant is found in the general population with an overall allele frequency of 0.028% (49/177946 alleles) in the Genome Aggregation Database. The threonine at codon 72 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.309). Due to limited information, the clinical significance of this variant is uncertain at this time.
Breakthrough Genomics, Breakthrough Genomics	RCV000676026	SCV005188077	uncertain significance	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000676026	SCV000801760	uncertain significance	not provided	2017-05-10	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000676026	SCV001797994	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000676026	SCV001965345	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004757976	SCV005345261	uncertain significance	AGPS-related disorder	2024-06-27	no assertion criteria provided	clinical testing	The AGPS c.214A>G variant is predicted to result in the amino acid substitution p.Thr72Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.055% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.