NM_000262.3(NAGA):c.983T>C (p.Met328Thr) AND Alpha-N-acetylgalactosaminidase deficiency type 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 30, 2021
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:: RCV001305248.5

Allele description [Variation Report for NM_000262.3(NAGA):c.983T>C (p.Met328Thr)]

NM_000262.3(NAGA):c.983T>C (p.Met328Thr)

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.983T>C (p.Met328Thr)

HGVS:

NC_000022.11:g.42061042A>G
NG_009247.1:g.14801T>C
NM_000262.3:c.983T>CMANE SELECT
NM_001362848.1:c.983T>C
NM_001362850.1:c.983T>C
NP_000253.1:p.Met328Thr
NP_001349777.1:p.Met328Thr
NP_001349779.1:p.Met328Thr
NC_000022.10:g.42457046A>G
NM_000262.2:c.983T>C
p.Met328Thr

Protein change:

M328T

Links:

dbSNP: rs140356002

NCBI 1000 Genomes Browser:

rs140356002

Molecular consequence:

NM_000262.3:c.983T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001362848.1:c.983T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001362850.1:c.983T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Alpha-N-acetylgalactosaminidase deficiency type 1
Synonyms:: SCHINDLER DISEASE, TYPE I; ALPHA-N-ACETYLGALACTOSAMINIDASE DEFICIENCY, TYPE I; NAGA DEFICIENCY, TYPE I; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012221; MedGen: C1836544; Orphanet: 3137; Orphanet: 79279; Orphanet: 79281; OMIM: 609241

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001494577	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001494577

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 30, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001494577.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces methionine with threonine at codon 328 of the NAGA protein (p.Met328Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs140356002, ExAC 0.008%). This variant has not been reported in the literature in individuals affected with NAGA-related conditions. ClinVar contains an entry for this variant (Variation ID: 596276). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 16, 2023

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