Submissions for variant NM_000262.3(NAGA):c.973G>A (p.Glu325Lys)

gnomAD frequency: 0.00225  dbSNP: rs121434529

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256069	SCV000321922	pathogenic	not provided	2021-12-06	criteria provided, single submitter	clinical testing	Functional studies indicate this variant results in loss of alpha-N-acetylgalactosaminidase activity (Wang et al., 1990); This variant is associated with the following publications: (PMID: 17171432, 19683538, 29373990, 30487145, 8040340, 14685826, 8782044, 2243144, 11313741, 27138754, 29431110, 31980526, 31589614, 32860008)
Eurofins Ntd Llc (ga)	RCV000256069	SCV000331365	pathogenic	not provided	2016-08-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000501877	SCV000595898	pathogenic	Alpha-N-acetylgalactosaminidase deficiency	2016-03-25	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000019792	SCV000746490	uncertain significance	Alpha-N-acetylgalactosaminidase deficiency type 1	2020-05-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000019792	SCV000825839	pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 325 of the NAGA protein (p.Glu325Lys). This variant is present in population databases (rs121434529, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency (PMID: 1131374, 7707696, 8040340, 8071745). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18162). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NAGA function (PMID: 2243144, 8782044, 11313741). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000660647	SCV000893593	likely pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 2; Alpha-N-acetylgalactosaminidase deficiency type 1	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001148412	SCV001309305	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195394	SCV001365743	uncertain significance	not specified	2019-05-30	criteria provided, single submitter	clinical testing	The p.Glu325Lys variant in NAGA has been previously reported in 4 individuals with Schindler disease: 3 in the homozygous state from consanguineous families, and one in the compound heterozygous state with another presumably pathogenic NAGA variant and segregated with disease in 1 affected family member (Wang 1990, Keulemans 1996, Bakker 2001, Clark 2009). However two siblings of two affected individuals had the p.Glu325Lys variant (1 homozygote and 1 compound heterozygote) but were clinically unaffected, despite reduced enzyme activity (Wang 1990, Wang 1994, Keulemans 1996, Bakker 2001, Clark 2009). Thus, variable expressivity and reduced penetrance has been suggested to occur in Schindler disease. The p.Glu325Lys variant has also been identified in 0.4% (515/129126) European chromosomes by gnomAD (http://gnomad.broadinstitute.org/), which is significantly higher than the maximum expected allele frequency for a rare disease. Computational prediction tools and conservation analyses suggest this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Glu325Lys variant is uncertain due to conflicting evidence. ACMG/AMP criteria applied: PM3, PS3_Supporting, BS1, BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001148412	SCV001370663	pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 2	2020-05-11	criteria provided, single submitter	clinical testing	Variant summary: NAGA c.973G>A (p.Glu325Lys) results in a conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of 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 0.0025 in 251354 control chromosomes (gnomAD). c.973G>A has been reported in the literature in multiple individuals affected with alpha-N-Acetylgalactosamidase defiency, primarily with infantile-onset (AKA Schindler disease; examples- Wang_1990, Keulemans_1996, Bakker_2001, Chabas_2007). These data indicate that the variant is very likely to be associated with disease. The variant has also been detected as both homozygous (e.g. Keulemans_1996) and compound heterozygous (e.g. Bakker_2001) in asymptomatic siblings of children with Schindler disease, indicating that this variant may result in a spectrum of clinical presentations. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (examples: Wang_1990, Bakker_2001). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centogene AG - the Rare Disease Company	RCV000019792	SCV001426613	pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 1		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000256069	SCV001447717	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000019792	SCV001448884	likely pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 1	2018-03-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000256069	SCV001713912	pathogenic	not provided	2022-04-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000256069	SCV002017886	likely pathogenic	not provided	2021-12-27	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000660647	SCV002061521	likely pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 2; Alpha-N-acetylgalactosaminidase deficiency type 1	2021-08-12	criteria provided, single submitter	clinical testing	PS3, PP3, PM3
Mendelics	RCV001195394	SCV002518355	pathogenic	not specified	2023-03-30	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251915	SCV002523202	likely pathogenic	See cases	2019-07-07	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3, PM3, PP1, PP2, PP3
Genetics and Molecular Pathology, SA Pathology	RCV001148412	SCV002556529	likely pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 2	2021-10-27	criteria provided, single submitter	clinical testing	The NAGA c.973G>A variant is classified as Likely Pathogenic (PS3, PM3_S, PP3, PP5) This variant is a single nucleotide change from a guanine to an adenine at position 973 which is predicted to change the glutamic acid at position 325 in the protein to lysine. The variant has been reported in both the homozygous and compound heterozygous states in multiple individuals affected with alpha-NAGA deficiency, with variable expressivity and reduced penetrance (PMID: 2243144, 8782044, 1313741) (PM3_S). Functional studies demostrated that this variant results significantly reduced in the alpha-NAGA enzyme activity (PMID: 2243144, 8040340, 14685826) (PS3). The variant is in dbSNP (rs121434529) and has been reported in population databases (gnomAD (v3.1.2) 331/152198, 0 homozygote). The variant has been reported in ClinVar (ID: 18162) and HGMD (Accession: CM900169) as a disease causing variant (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000501877	SCV002769082	pathogenic	Alpha-N-acetylgalactosaminidase deficiency	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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 glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (696 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated alpha galactosidase A C-terminal beta sandwich domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many individuals with alpha-N-acetylgalactosaminidase (NAGA) deficiency and with variable clinical presentation (ClinVar, PMIDs: 11313741, 17171432). PMID:11313741 reported this variant as homozygous in a 3-year old proband with congenital cataract, slight motor retardation and secondary demyelinisation, and his 7-year old healthy sibling; both siblings had undetectable/profound deficiency in NAGA activity. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Profound NAGA enzyme deficiency has been reported in tissue samples from individuals who are homozygous or compound heterozygous with this variant (PMIDs: 11313741, 17171432). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen	RCV000256069	SCV004153179	likely pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	NAGA: PP1:Strong, PS3:Moderate, PM2:Supporting, PM3:Supporting
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001148412	SCV004804742	likely pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 2	2024-03-17	criteria provided, single submitter	research
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000019792	SCV004807878	likely pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 1	2024-03-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018646	SCV004961145	pathogenic	Inborn genetic diseases	2020-12-11	criteria provided, single submitter	clinical testing	The c.973G>A (p.E325K) alteration is located in exon 8 (coding exon 8) of the NAGA gene. This alteration results from a G to A substitution at nucleotide position 973, causing the glutamic acid (E) at amino acid position 325 to be replaced by a lysine (K). This mutation was identified in the homozygous state in multiple individuals with alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency and has been shown to segregate with disease (van Diggelen, 1987; Bakker, 2001). In one family, a sibling was clinically unaffected with negligible enzymatic activity, suggesting variable expressivity (Bakker, 2001). The p.E325K alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000019792	SCV000040090	pathogenic	Alpha-N-acetylgalactosaminidase deficiency type 1	2001-02-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004734526	SCV005345293	pathogenic	NAGA-related disorder	2024-09-03	no assertion criteria provided	clinical testing	The NAGA c.973G>A variant is predicted to result in the amino acid substitution p.Glu325Lys. This variant has been reported in the homozygous or compound heterozygous state in patients with enzymatic and/or biochemical test results consistent with alpha-N-acetylgalactosaminidase deficiency (Wang et al. 1990. PubMed ID: 2243144; Keulemans et al. 1996. PubMed ID: 8782044; Bakker et al. 2001. PubMed ID: 11313741; Chabás et al. 2007. PubMed ID: 17171432). In all of those studies, the p.Glu325Lys variant was reported to reduce enzyme activity to <1% of wild-type. Of note, the c.973G>A variant has been reported at an allele frequency of up to 0.41% in a large population database, which is relatively high for a pathogenic variant. However, based on its effect on NAGA enzyme activity, we classify the c.973G>A (p.Glu325Lys) variant as pathogenic.