ClinVar Miner

Submissions for variant NM_000027.4(AGA):c.488G>C (p.Cys163Ser) (rs121964904)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Myriad Women's Health, Inc. RCV000410114 SCV001193819 pathogenic Aspartylglucosaminuria 2019-12-19 criteria provided, single submitter clinical testing NM_000027.3(AGA):c.488G>C(C163S) is classified as pathogenic in the context of aspartylglucosaminuria. Sources cited for classification include the following: PMID 11309371, 1904874, 1559710, 1765378 and 9742145. Classification of NM_000027.3(AGA):c.488G>C(C163S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000410114 SCV001207113 pathogenic Aspartylglucosaminuria 2020-07-21 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 163 of the AGA protein (p.Cys163Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs121964904, ExAC 0.8%). This variant has been observed to be homozygous and in combination with another AGA variant in numerous individuals and families affected with aspartylglucosaminuria (PMID: 1904874, 2011603, 1703489, 21228398, 11309371, 7627186). This variant is known in the literature as AGAFin, and is a common pathogenic variant in individuals of Finnish ancestry. Of note, this variant frequently co-occurs in cis with the functionally Benign AGA p.Arg161Gln variant (PMID: 27876883). ClinVar contains an entry for this variant (Variation ID: 219). This variant has been reported to affect AGA protein function (PMID: 1904874, 1765378, 8172656). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410114 SCV001467838 pathogenic Aspartylglucosaminuria 2020-12-16 criteria provided, single submitter clinical testing Variant summary: AGA c.488G>C (p.Cys163Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 251288 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.488G>C has been reported in the literature in the compound heterozygous and homozygous state in multiple individuals affected with Aspartylglucosaminuria (Fisher_1991, Ikonen_1991, Tollersrud_1994, Saarela_2001). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant impaired processing of the precursor molecule into subunits and reduced AGA activity (Fish_1991, Riikonen_1994, Banning_2016). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000243 SCV000020387 pathogenic Aspartylglucosaminuria, finnish type 1995-01-01 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000410114 SCV001142339 likely pathogenic Aspartylglucosaminuria 2020-01-06 no assertion criteria provided curation NM_000027.3:c.488G>C in the AGA gene has an allele frequency of 0.008 in European (Finnish) subpopulation in the gnomAD database. The c.488G>C (p.Cys163Ser) variant has been reported previously in the compound heterozygous states (C163S/R161Q) in association with aspartylglucosaminuria (PMID: 1904874; 7627186; 2011603). In vitro functional studies demonstrated that p.Cys163Ser results in deficient enzyme activity (PMID: 1904874; 1765378). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3; PS3; PP4.

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