NM_000203.5(IDUA):c.1469T>C (p.Leu490Pro) AND Hurler syndrome

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: May 22, 2022
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:: RCV000173657.16

Allele description [Variation Report for NM_000203.5(IDUA):c.1469T>C (p.Leu490Pro)]

NM_000203.5(IDUA):c.1469T>C (p.Leu490Pro)

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.1469T>C (p.Leu490Pro)

HGVS:

NC_000004.12:g.1003102T>C
NG_008103.1:g.21106T>C
NM_000203.4(IDUA):c.1469T>C
NM_000203.5:c.1469T>CMANE SELECT
NM_001363576.1:c.1073T>C
NP_000194.2:p.Leu490Pro
NP_000194.2:p.Leu490Pro
NP_001350505.1:p.Leu358Pro
LRG_1277t1:c.1469T>C
LRG_1277:g.21106T>C
LRG_1277p1:p.Leu490Pro
NC_000004.11:g.996890T>C
NM_000203.3:c.1469T>C
NM_000203.4(IDUA):c.1469T>C
NM_000203.4:c.1469T>C
NM_000203.5:c.1469T>C
NR_110313.1:n.1557T>C
P35475:p.Leu490Pro

Protein change:

L358P; LEU490PRO

Links:

UniProtKB: P35475#VAR_003374; OMIM: 252800.0012; dbSNP: rs121965027

NCBI 1000 Genomes Browser:

rs121965027

Molecular consequence:

NM_000203.5:c.1469T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363576.1:c.1073T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_110313.1:n.1557T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

Unknown function

Observations:

Condition(s)

Name:: Hurler syndrome
Synonyms:: MUCOPOLYSACCHARIDOSIS TYPE IH; Gargoylism, Hurler Syndrome
Identifiers:: MONDO: MONDO:0011758; MedGen: C0086795; OMIM: 607014

Recent activity

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Homo sapiens serine and arginine rich splicing factor 11 (SRSF11), transcript va...
Homo sapiens serine and arginine rich splicing factor 11 (SRSF11), transcript variant 16, mRNA
gi|2027535409|ref|NM_001394402.1|

Nucleotide
PREDICTED: Homo sapiens serine and arginine rich splicing factor 11 (SRSF11), tr...
PREDICTED: Homo sapiens serine and arginine rich splicing factor 11 (SRSF11), transcript variant X9, mRNA
gi|2217272334|ref|XM_047434536.1|

Nucleotide
Rattus norvegicus DNA fragmentation factor subunit beta (Dffb), mRNA
Rattus norvegicus DNA fragmentation factor subunit beta (Dffb), mRNA
gi|1937369980|ref|NM_053362.2|

Nucleotide
Human DNA sequence from clone RP4-677H15 on chromosome 1p31.3-32.3, complete seq...
Human DNA sequence from clone RP4-677H15 on chromosome 1p31.3-32.3, complete sequence
gi|8894296|emb|AL353771.8|

Nucleotide
ND4L [Oratosquilla oratoria]
ND4L [Oratosquilla oratoria]
Gene ID:9481014

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000799455	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Apr 18, 2018)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21394825, 23084433, 7550232, 27146977, 17570076 Citation Link,
SCV001870413	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002521779	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17570076, 23786846, 7550232, 21394825, 28752568, 11735025, 27146977, 25741868
SCV003845954	Molecular Biology Laboratory, Department of Zoology, Quaid-i-azam University	no assertion criteria provided	Pathogenic	inherited	research
SCV004100363	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	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	inherited	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Hindu	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Heparan sulfate and dermatan sulfate derived disaccharides are sensitive markers for newborn screening for mucopolysaccharidoses types I, II and III.

de Ruijter J, de Ru MH, Wagemans T, Ijlst L, Lund AM, Orchard PJ, Schaefer GB, Wijburg FA, van Vlies N.

Mol Genet Metab. 2012 Dec;107(4):705-10. doi: 10.1016/j.ymgme.2012.09.024. Epub 2012 Sep 28.

PubMed [citation]

PMID:: 23084433

Enzyme replacement therapy in 12 patients with MPS I-H/S with homozygous p.Leu490Pro mutation.

Arora RS, Mercer J, Thornley M, Tylee K, Wraith JE.

J Inherit Metab Dis. 2007 Oct;30(5):821. Epub 2007 Jun 14.

PubMed [citation]

PMID:: 17570076

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000799455.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

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

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV001870413.1

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

Description

A homozygous missense variant in exon 10 of the IDUA gene that results in the amino acid substitution of Proline for Leucine at codon 490 was detected. The observed variant c.1469T>C:p.(Leu490Pro) has not been reported in the 1000 genomes and has a MAF of 0.002% in the ExAC databases. The in silico prediction of the variant is damaging by PROVEAN and MutationTaster2. In summary, the variant meets our criteria to be classified as pathogenic.

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

From 3billion, SCV002521779.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:23786846). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011919). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:11735025, 17570076, 21394825, 27146977, 28752568, 7550232). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID:, 21394825, 27146977, 28752568). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Molecular Biology Laboratory, Department of Zoology, Quaid-i-azam University, SCV003845954.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004100363.1

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

Description

The missense variant p.L490P in IDUA (NM_000203.4) has been reported previously in multiple patients in homozygous state including those of Indian origin (Uttarilli A et al,2016). Although the variant is present at 0.0047% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.L490P variant is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between leucine and proline. For these reasons, this variant has been classified as Likely Pathogenic.

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

Last Updated: Nov 10, 2024

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