Submissions for variant NM_000027.4(AGA):c.346C>T (p.Arg116Trp)

dbSNP: rs386833423

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049351	SCV001574483	likely pathogenic	Aspartylglucosaminuria	2023-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 116 of the AGA protein (p.Arg116Trp). This variant is present in population databases (rs386833423, gnomAD 0.0009%). This missense change has been observed in individual(s) with aspartylglucosaminuria (PMID: 23271757). ClinVar contains an entry for this variant (Variation ID: 55942). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AGA protein function. Experimental studies have shown that this missense change affects AGA function (PMID: 27876883). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000049351	SCV002104010	pathogenic	Aspartylglucosaminuria	2022-02-02	criteria provided, single submitter	clinical testing	Variant summary: AGA c.346C>T (p.Arg116Trp) 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 4e-06 in 251442 control chromosomes. c.346C>T has been reported in the literature as a homozygous genotype in three siblings from at-least one consanguineous Turkish family affected with Aspartylglucosaminuria and has been cited by others (example, Opaladen_2014 and Goodspeed_2021). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <5% of normal activity in leukocytes, fibroblasts and in-vitro (example, Opaladen_2014, Banning_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000049351	SCV004217772	likely pathogenic	Aspartylglucosaminuria	2024-02-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV004546425	SCV005042519	likely pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	AGA: PM2, PM3, PP4, PS3:Supporting
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049351	SCV000081783	probable-pathogenic	Aspartylglucosaminuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.