NM_000203.5(IDUA):c.1099_1100delinsTT (p.Ala367Leu) AND Mucopolysaccharidosis type 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 24, 2023
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:: RCV003755012.3

Allele description [Variation Report for NM_000203.5(IDUA):c.1099_1100delinsTT (p.Ala367Leu)]

NM_000203.5(IDUA):c.1099_1100delinsTT (p.Ala367Leu)

Gene:

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

Variant type:

Indel

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_000203.5(IDUA):c.1099_1100delinsTT (p.Ala367Leu)

HGVS:

NC_000004.12:g.1002395_1002396delinsTT
NG_008103.1:g.20399_20400delinsTT
NM_000203.5:c.1099_1100delinsTTMANE SELECT
NM_001363576.1:c.703_704delinsTT
NP_000194.2:p.Ala367Leu
NP_001350505.1:p.Ala235Leu
LRG_1277t1:c.1099_1100delinsTT
LRG_1277:g.20399_20400delinsTT
LRG_1277p1:p.Ala367Leu
NC_000004.11:g.996183_996184delinsTT
NR_110313.1:n.1187_1188delinsTT

Protein change:

A235L

Molecular consequence:

NM_000203.5:c.1099_1100delinsTT - missense variant - [Sequence Ontology: SO:0001583]
NM_001363576.1:c.703_704delinsTT - missense variant - [Sequence Ontology: SO:0001583]
NR_110313.1:n.1187_1188delinsTT - 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
SCV004379254	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 24, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22112002, 27392569, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004379254

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 24, 2023)

germline

clinical testing

PubMed (3)
[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

Variable disease progression after successful stem cell transplantation: prospective follow-up investigations in eight patients with Hurler syndrome.

Grigull L, Sykora KW, Tenger A, Bertram H, Meyer-Marcotty M, Hartmann H, Bültmann E, Beilken A, Zivicnjak M, Mynarek M, Osthaus AW, Schilke R, Kollewe K, Lücke T.

Pediatr Transplant. 2011 Dec;15(8):861-9. doi: 10.1111/j.1399-3046.2011.01595.x.

PubMed [citation]

PMID:: 22112002

Musculoskeletal manifestations in mucopolysaccharidosis type I (Hurler syndrome) following hematopoietic stem cell transplantation.

Schmidt M, Breyer S, Löbel U, Yarar S, Stücker R, Ullrich K, Müller I, Muschol N.

Orphanet J Rare Dis. 2016 Jul 8;11(1):93. doi: 10.1186/s13023-016-0470-7.

PubMed [citation]

PMID:: 27392569
PMCID:: PMC4938899

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004379254.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces alanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 367 of the IDUA protein (p.Ala367Leu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with IDUA-related conditions. ClinVar contains an entry for this variant (Variation ID: 2432776). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. This variant disrupts the p.Ala367 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22112002, 27392569; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Sep 29, 2024

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