NM_000203.5(IDUA):c.1709A>T (p.Asp570Val) AND Mucopolysaccharidosis type 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 27, 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:: RCV002761384.3

Allele description [Variation Report for NM_000203.5(IDUA):c.1709A>T (p.Asp570Val)]

NM_000203.5(IDUA):c.1709A>T (p.Asp570Val)

Gene:

IDUA:alpha-L-iduronidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_000203.5(IDUA):c.1709A>T (p.Asp570Val)

HGVS:

NC_000004.12:g.1003607A>T
NG_008103.1:g.21611A>T
NG_101700.1:g.496A>T
NM_000203.5:c.1709A>TMANE SELECT
NM_001363576.1:c.1313A>T
NP_000194.2:p.Asp570Val
NP_001350505.1:p.Asp438Val
LRG_1277t1:c.1709A>T
LRG_1277:g.21611A>T
LRG_1277p1:p.Asp570Val
NC_000004.11:g.997395A>T
NR_110313.1:n.1797A>T

Protein change:

D438V

Molecular consequence:

NM_000203.5:c.1709A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363576.1:c.1313A>T - missense variant - [Sequence Ontology: SO:0001583]
NR_110313.1:n.1797A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mucopolysaccharidosis type 1
Synonyms:: Mucopolysaccharidosis type I; MPS 1; Attenuated MPS I (subtype); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0001586; MedGen: C0023786

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003023975	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 27, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25558755, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003023975

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 27, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Mutation c.1190-1delG/N in intron 8 and c.1708G>C/N in exon 12 not reported in the IDUA gene developed a clinical phenotype of Scheie syndrome.

Delgado Luengo WN, Miranda Contreras LE, Chávez CJ, Solis-Añez E, Cammarata-Scalisi F.

Invest Clin. 2014 Dec;55(4):365-70.

PubMed [citation]

PMID:: 25558755

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003023975.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. This variant disrupts the p.Asp570 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25558755). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 IDUA protein function. This variant has not been reported in the literature in individuals affected with IDUA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 570 of the IDUA protein (p.Asp570Val).

#	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: Sep 29, 2024

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