Submissions for variant NM_000027.4(AGA):c.800dup (p.Pro268fs)

gnomAD frequency: 0.00001  dbSNP: rs386833436

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000000249	SCV000485780	likely pathogenic	Aspartylglucosaminuria	2016-02-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000249	SCV000918397	pathogenic	Aspartylglucosaminuria	2018-04-11	criteria provided, single submitter	clinical testing	Variant summary: AGA c.800dupT (p.Pro268AlafsX52) 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, which are commonly known mechanisms for disease. The variant was observed with an allele freqyency of 2.8e-05 in 246258 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in AGA causing Aspartylglucosaminuria (2.8e-05 vs 0.0049), allowing no conclusion about variant significance. The variant, c.800dupT, has been reported in the literature in a homozygous individual affected with Aspartylglucosaminuria, who presented with less than 10% normal AGA activity (Ikonen_1991). These data indicate that the variant may be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000249	SCV001415728	pathogenic	Aspartylglucosaminuria	2024-04-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro268Alafs*52) in the AGA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the AGA protein. This variant is present in population databases (rs386833436, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with aspartylglucosaminuria (PMID: 1722323). ClinVar contains an entry for this variant (Variation ID: 225). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects AGA function (PMID: 1722323, 11309371). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002512599	SCV003742654	pathogenic	Inborn genetic diseases	2021-02-11	criteria provided, single submitter	clinical testing	The c.800dupT (p.P268Afs*52) alteration, located in exon 7 (coding exon 7) of the AGA gene, consists of a duplication of T at position 800, causing a translational frameshift with a predicted alternate stop codon after 52 amino acids. This alteration occurs at the 3' terminus of the AGA gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 79 amino acids of the protein. However, premature stop codons are typically deleterious in nature. Based on data from the Genome Aggregation Database (gnomAD) database, the AGA c.800dupT alteration was observed in 0.003% (7/251484) of total alleles studied, with a frequency of 0.02% (6/34592) in the Latino subpopulation. This alteration has been detected in a homozygous state in an individual with aspartylglucosaminidase, which was diagnosed via clinical features, detection of urinary glycoasparagines, and decreased AGA activity (Ikonen, 1991). This amino acid position is highly conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity	RCV000000249	SCV003816664	pathogenic	Aspartylglucosaminuria	2023-02-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000249	SCV004217571	pathogenic	Aspartylglucosaminuria	2024-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV004721239	SCV005327052	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 11309371); Frameshift variant predicted to result in abnormal protein length as the last 79 amino acids are replaced with 51 different amino acids, and other similar variants have been reported in HGMD; Also known as c.800_801insT; This variant is associated with the following publications: (PMID: 1722323, 11309371)
OMIM	RCV000000249	SCV000020393	pathogenic	Aspartylglucosaminuria	1991-12-15	no assertion criteria provided	literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000000249	SCV000081796	probable-pathogenic	Aspartylglucosaminuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.