Submissions for variant NM_000262.3(NAGA):c.479C>G (p.Ser160Cys)

gnomAD frequency: 0.00052  dbSNP: rs121434532

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169668	SCV000221201	likely pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 1	2013-11-26	criteria provided, single submitter	clinical testing	The Ser160Cys variant in NAGA has been previously identified in 1 compound heterozygous individual with Alpha-N-acetylgalactosaminidase (NAGA) deficiency and segregated with enzyme deficiency in a sibling (Keulemans 1996). Functional studies indicate this variant results in 4% residual NAGA activity possibly explaining the milder than typical phenotype, particularly in the clinically unaffected sibling with reduced enzyme activity (Keulemans 1996). In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance.
CeGaT Center for Human Genetics Tuebingen	RCV001092858	SCV001249564	pathogenic	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000169668	SCV001306454	uncertain significance	Alpha-N-acetylgalactosaminidase deficiency type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001145759	SCV001306455	uncertain significance	Alpha-N-acetylgalactosaminidase deficiency type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV000169668	SCV001509069	uncertain significance	Alpha-N-acetylgalactosaminidase deficiency type 1	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 160 of the NAGA protein (p.Ser160Cys). This variant is present in population databases (rs121434532, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with alpha-NAGA deficiency (PMID: 8782044). 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: 18165). 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 NAGA protein function. Experimental studies have shown that this missense change affects NAGA function (PMID: 8071745, 8782044, 23045655). 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.
GeneDx	RCV001092858	SCV001986159	uncertain significance	not provided	2018-04-25	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19683538, 27138754, 23045655, 8782044, 11313741, 31980526, 31589614)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778658	SCV002015012	uncertain significance	not specified	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: NAGA c.479C>G (p.Ser160Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 251336 control chromosomes (gnomAD). c.479C>G has been reported in the literature as a compound heterozygous genotype in two siblings only one of whom was affected while the other remained unaffected at-least 5 years after initial follow up (example, Keulmans_1996, Bakker_2001). Although the alpha-NAGA activity in fibroblasts from the affected sibling was 4% of wild-type levels, the activity of the unaffected sibling was not reported. Therefore this does not support a variant specific impact on function. These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Clark_2012). The following publications have been ascertained in the context of this evaluation (PMID: 11313741, 34670123, 31980526, 23045655, 8782044, 11251574, 8071745). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=2) or VUS (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV001092858	SCV002017887	likely pathogenic	not provided	2022-12-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001092858	SCV002541729	uncertain significance	not provided	2021-05-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272026	SCV002557615	uncertain significance	Alpha-N-acetylgalactosaminidase deficiency	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-N-acetylgalactosaminidase deficiency (MONDO#0017779). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The clinical heterogeneity among individuals with alpha-N-acetylgalactosaminidase ranges from 'non-disease' to infantile neuroaxonal dystrophy (PMID:11313741). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (215 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Melibiase_2 (galactosidase A) domain (NCBI, DECIPHER, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity. This variant has been reported as likely pathogenic or pathogenic (at least 5 times) and as a VUS (at least 5 times) across ClinVar and LOVD. In the literature, it has been reported in 2 siblings who were compound heterozygous for this variant and p.(Glu325Lys). However, only one sibling was reported as being clinically affected. The other sibling with the same genotype did not present with overt clinical symptoms at time of examination (PMID: 8782044; 11313741) (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Reduced α-NAGA activity in fibroblasts of one sibling compound heterozygous for p.(Ser160Cys) and p.(Glu325Lys). α-NAGA activity of the unaffected sibling was not tested (PMID: 8782044). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000019795	SCV000040093	pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 3	1996-06-01	no assertion criteria provided	literature only