NM_152419.3(HGSNAT):c.1445T>A (p.Met482Lys) AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Aug 23, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001378638.1

Allele description [Variation Report for NM_152419.3(HGSNAT):c.1445T>A (p.Met482Lys)]

NM_152419.3(HGSNAT):c.1445T>A (p.Met482Lys)

Gene:
HGSNAT:heparan-alpha-glucosaminide N-acetyltransferase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
8p11.21
Genomic location:
Preferred name:
NM_152419.3(HGSNAT):c.1445T>A (p.Met482Lys)
Other names:
M510K
HGVS:
  • NC_000008.11:g.43193824T>A
  • NG_009552.1:g.58376T>A
  • NM_001363227.2:c.1445T>A
  • NM_001363228.2:c.1253T>A
  • NM_001363229.2:c.581T>A
  • NM_152419.3:c.1445T>AMANE SELECT
  • NP_001350156.1:p.Met482Lys
  • NP_001350157.1:p.Met418Lys
  • NP_001350158.1:p.Met194Lys
  • NP_689632.2:p.Met482Lys
  • NC_000008.10:g.43048967T>A
Protein change:
M194K; MET510LYS
Links:
OMIM: 610453.0005; dbSNP: rs121908284
NCBI 1000 Genomes Browser:
rs121908284
Molecular consequence:
  • NM_001363227.2:c.1445T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363228.2:c.1253T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363229.2:c.581T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_152419.3:c.1445T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Mucopolysaccharidosis, MPS-III-C (MPS3C)
Synonyms:
Mucopoly-saccharidosis type 3C; Sanfilippo syndrome C; Acetyl-CoA alpha-glucosaminide n-acetyltransferase deficiency; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009657; MedGen: C0086649; Orphanet: 581; Orphanet: 79271; OMIM: 252930
Name:
Retinitis pigmentosa 73 (RP73)
Identifiers:
MONDO: MONDO:0014687; MedGen: C4225287; Orphanet: 791; OMIM: 616544

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001576254Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 23, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome).

Hrebícek M, Mrázová L, Seyrantepe V, Durand S, Roslin NM, Nosková L, Hartmannová H, Ivánek R, Cízkova A, Poupetová H, Sikora J, Urinovská J, Stranecký V, Zeman J, Lepage P, Roquis D, Verner A, Ausseil J, Beesley CE, Maire I, Poorthuis BJ, van de Kamp J, et al.

Am J Hum Genet. 2006 Nov;79(5):807-19. Epub 2006 Sep 8.

PubMed [citation]
PMID:
17033958
PMCID:
PMC1698556

Protein misfolding as an underlying molecular defect in mucopolysaccharidosis III type C.

Feldhammer M, Durand S, Pshezhetsky AV.

PLoS One. 2009 Oct 13;4(10):e7434. doi: 10.1371/journal.pone.0007434.

PubMed [citation]
PMID:
19823584
PMCID:
PMC2757673
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001576254.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces methionine with lysine at codon 482 of the HGSNAT protein (p.Met482Lys). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) withmucopolysaccharidosis type IIIC (PMID: 17033958). This variant is also known as c.1529T>A, p.M510K. ClinVar contains an entry for this variant (Variation ID: 1234). 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 expected to disrupt HGSNAT protein function. Experimental studies have shown that this variant affects HGSNAT protein function (PMID: 19823584, 20583299). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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

Last Updated: Oct 7, 2021

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