Submissions for variant NM_000027.4(AGA):c.503G>A (p.Trp168Ter)

gnomAD frequency: 0.00002  dbSNP: rs386833430

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000049358	SCV000220289	likely pathogenic	Aspartylglucosaminuria	2014-05-01	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049358	SCV002041747	pathogenic	Aspartylglucosaminuria	2021-11-05	criteria provided, single submitter	clinical testing	Variant summary: AGA c.503G>A (p.Trp168X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 250860 control chromosomes (gnomAD). c.503G>A has been reported in the literature in at least two individuals affected with Aspartylglucosaminuria (examples: Saarela_2001, Banning_2018). Experimental evidence evaluating an impact on protein function demonstrated the variant confers minimal enzymatic activity (Saarela_2001, Banning_2018). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000049358	SCV002237710	pathogenic	Aspartylglucosaminuria	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp168*) in the AGA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AGA are known to be pathogenic (PMID: 7627186, 11309371). This variant is present in population databases (rs386833430, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with aspartylglucosaminuria (PMID: 11309371, 29247835). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 55949). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002513680	SCV003568080	likely pathogenic	Inborn genetic diseases	2021-09-14	criteria provided, single submitter	clinical testing	The c.503G>A (p.W168*) alteration, located in exon 4 (coding exon 4) of the AGA gene, consists of a G to A substitution at nucleotide position 503. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 168. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant has been detected in the heterozygous and compound heterozygous state in individuals with aspartylglucosaminuria (Saarela, 2001; Banning, 2018). In vitro studies have shown that this alteration impacts AGA protein function (Saarela, 2001). Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV000049358	SCV004217627	pathogenic	Aspartylglucosaminuria	2023-08-23	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049358	SCV000081790	probable-pathogenic	Aspartylglucosaminuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000049358	SCV004171567	pathogenic	Aspartylglucosaminuria	2023-11-24	no assertion criteria provided	clinical testing