NM_000203.5(IDUA):c.1163C>A (p.Thr388Lys) AND Mucopolysaccharidosis type 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001249042.8

Allele description [Variation Report for NM_000203.5(IDUA):c.1163C>A (p.Thr388Lys)]

NM_000203.5(IDUA):c.1163C>A (p.Thr388Lys)

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.1163C>A (p.Thr388Lys)

HGVS:

NC_000004.12:g.1002459C>A
NG_008103.1:g.20463C>A
NM_000203.5:c.1163C>AMANE SELECT
NM_001363576.1:c.767C>A
NP_000194.2:p.Thr388Lys
NP_001350505.1:p.Thr256Lys
LRG_1277t1:c.1163C>A
LRG_1277:g.20463C>A
LRG_1277p1:p.Thr388Lys
NC_000004.11:g.996247C>A
NC_000004.11:g.996247C>A
NM_000203.3:c.1163C>A
NM_000203.4(IDUA):c.1163C>A
NR_110313.1:n.1251C>A
p.Thr388Lys

Protein change:

T256K

Links:

dbSNP: rs794727896

NCBI 1000 Genomes Browser:

rs794727896

Molecular consequence:

NM_000203.5:c.1163C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363576.1:c.767C>A - missense variant - [Sequence Ontology: SO:0001583]
NR_110313.1:n.1251C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mucopolysaccharidosis type 1 (MPS1)
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
SCV001422980	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 13, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 27520059, 25741868 Citation Link,
SCV002241296	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 27520059, 31194252, 14516901, 17606547, 21253827, 21963080, 28752568, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001422980

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 13, 2020)

germline

curation

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

Citation Link,

SCV002241296

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 17, 2023)

germline

clinical testing

PubMed (8)
[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, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Report of 5 novel mutations of the α-L-iduronidase gene and comparison of Korean mutations in relation with those of Japan or China in patients with mucopolysaccharidosis I.

Kwak MJ, Huh R, Kim J, Park HD, Cho SY, Jin DK.

BMC Med Genet. 2016 Aug 12;17(1):58. doi: 10.1186/s12881-016-0319-x.

PubMed [citation]

PMID:: 27520059
PMCID:: PMC4983032

See all PubMed Citations (9)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422980.2

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

Description

The p.Thr388Lys variant in IDUA has been reported in 1 individual with mucopolysaccharidosis (MPS) (PMID: 27520059) and has been identified in 0.009% (1/10974) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs794727896). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 198686) as a VUS by Counsyl and as likely pathogenic by EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Thr388Arg, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 28752568, 21963080, 28728811; Variation ID: 496834). The presence of this variant in 1 affected homozygote with MPS increases the likelihood that the p.Thr388Lys variant is pathogenic (PMID: 27520059). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PP3, PM3_supporting (Richards 2015).

#	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

From Invitae, SCV002241296.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 388 of the IDUA protein (p.Thr388Lys). This variant is present in population databases (rs794727896, gnomAD 0.01%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 27520059, 31194252). ClinVar contains an entry for this variant (Variation ID: 198696). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. This variant disrupts the p.Thr388 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14516901, 17606547, 21253827, 21963080, 28752568). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

#	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: Mar 30, 2024

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