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NM_000262.3(NAGA):c.479C>G (p.Ser160Cys) AND Alpha-N-acetylgalactosaminidase deficiency

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jun 24, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002272026.5

Allele description [Variation Report for NM_000262.3(NAGA):c.479C>G (p.Ser160Cys)]

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

Genes:
LOC126863160:CDK7 strongly-dependent group 2 enhancer GRCh37_chr22:42462918-42464117 [Gene]
NAGA:alpha-N-acetylgalactosaminidase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
22q13.2
Genomic location:
Preferred name:
NM_000262.3(NAGA):c.479C>G (p.Ser160Cys)
HGVS:
  • NC_000022.11:g.42067136G>C
  • NG_009247.1:g.8707C>G
  • NM_000262.3:c.479C>GMANE SELECT
  • NM_001362848.1:c.479C>G
  • NM_001362850.1:c.479C>G
  • NP_000253.1:p.Ser160Cys
  • NP_001349777.1:p.Ser160Cys
  • NP_001349779.1:p.Ser160Cys
  • NC_000022.10:g.42463140G>C
  • NM_000262.2:c.479C>G
  • P17050:p.Ser160Cys
Protein change:
S160C; SER160CYS
Links:
UniProtKB: P17050#VAR_000496; OMIM: 104170.0004; dbSNP: rs121434532
NCBI 1000 Genomes Browser:
rs121434532
Molecular consequence:
  • NM_000262.3:c.479C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362848.1:c.479C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001362850.1:c.479C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Alpha-N-acetylgalactosaminidase deficiency
Identifiers:
MONDO: MONDO:0017779; MedGen: C5848084

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002557615Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jun 24, 2022) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype.

Keulemans JL, Reuser AJ, Kroos MA, Willemsen R, Hermans MM, van den Ouweland AM, de Jong JG, Wevers RA, Renier WO, Schindler D, Coll MJ, Chabas A, Sakuraba H, Suzuki Y, van Diggelen OP.

J Med Genet. 1996 Jun;33(6):458-64.

PubMed [citation]
PMID:
8782044
PMCID:
PMC1050630

Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: no association with neuroaxonal dystrophy?

Bakker HD, de Sonnaville ML, Vreken P, Abeling NG, Groener JE, Keulemans JL, van Diggelen OP.

Eur J Hum Genet. 2001 Feb;9(2):91-6.

PubMed [citation]
PMID:
11313741
See all PubMed Citations (3)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557615.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 13, 2025