rs121965027

chr4-1003102-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000203.5(IDUA):c.1469T>C(p.Leu490Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,512,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L490L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 0.942

Genes affected

IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000203.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 4-1003102-T-C is Pathogenic according to our data. Variant chr4-1003102-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.1469T>C	p.Leu490Pro	missense_variant	10/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.1469T>C	p.Leu490Pro	missense_variant	10/14	2	NM_000203.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151002 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000220 AC: 30 AN: 1361714 Hom.: 0 Cov.: 37 AF XY: 0.0000370 AC XY: 25 AN XY: 675832

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000393

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151002 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73728

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000872 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hurler syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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. -
Pathogenic, no assertion criteria provided	research	Molecular Biology Laboratory, Department of Zoology, Quaid-i-azam University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 18, 2018	- -

Mucopolysaccharidosis type 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 14, 2020	The p.Leu490Pro variant in IDUA has been reported in at least 20 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 7550232, 11735025, 21394825) and has been Identified in 0.026% (6/22666) of South Asian chromosomes and 0.001% (1/69396) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965027). 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: 11919) as Pathogenic by EGL Genetic Diagnostics, Counsyl, and OMIM. In vitro functional studies provide some evidence that the p.Leu490Pro variant may impact protein function (PMID: 7550232). However, these types of assays may not accurately represent biological function. The phenotype of individuals homozygous for this variant is highly specific for MPS1 based on alpha-l-iduronidase activity being <1% of normal consistent with disease (PMID: 27146977). The presence of this variant in at least 19 affected homozygotes and in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Leu490Pro variant is pathogenic (VariationID: 556406; PMID: 28752568, 7550232, 11735025, 21394825, 27146977). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PS3_moderate, PM2_supporting, PP4 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 490 of the IDUA protein (p.Leu490Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 7550232, 21394825, 27146977). ClinVar contains an entry for this variant (Variation ID: 11919). 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. Experimental studies have shown that this missense change affects IDUA function (PMID: 7550232). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2023	Variant summary: IDUA c.1469T>C (p.Leu490Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 149530 control chromosomes (gnomAD). c.1469T>C has been reported in the literature in multiple individuals affected with attenuated Hurler Scheie (example: Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Oussorena_2013). The following publications have been ascertained in the context of this evaluation (PMID: 28752568, 23786846). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 07, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2022	Published functional studies demonstrate this variant results in reduced IDUA activity (Tieu et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28752568, 27146977, 21394825, 31400021, 31473686, 31589614, 23786846, 7550232) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2012	- -

Mucopolysaccharidosis, MPS-I-H/S Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	17
Dann	Benign	0.45
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.56	T;.
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.026	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.0000027	A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.19	T;T
Sift4G	Uncertain	0.041	D;T
Polyphen		0.076	B;.
Vest4		0.72
MVP		0.83
MPC		0.32
ClinPred		0.84	D
GERP RS		-0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121965027; hg19: chr4-996890;