4-1003418-C-T

Position:

• chr4-1003418-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000203.5(IDUA):​c.1598C>T​(p.Pro533Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,376,970 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P533R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 2.91

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-1003418-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939
• PP5: Variant 4-1003418-C-T is Pathogenic according to our data. Variant chr4-1003418-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1598C>T	p.Pro533Leu	missense_variant	11/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1598C>T	p.Pro533Leu	missense_variant	11/14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1376970 Hom.: 0 Cov.: 33 AF XY: 0.00000147 AC XY: 1 AN XY: 679424

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro533 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301941, 10911525, 16435195, 21521498, 23786846, 24368159). 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 missense change has been observed in individuals with mucopolysaccharidosis (PMID: 9787109, 27511503). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 533 of the IDUA protein (p.Pro533Leu). -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The p.Pro533Leu variant in IDUA has been reported in 4 individuals with mucopolysaccharidosis (MPS) (PMID: 9787109, 27511503; doi: 10.7124/bc.00093B) and was absent from large population studies and no high quality genotypes at this site were noted to include this variant. This variant has also been reported in ClinVar (VariationID: 429205) 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.Pro533Arg, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 11910; PMID: 24036510, 28752568, 27196898, 19748810). The p.Pro533Leu variant is located in a region of IDUA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 24480078, 9787109, 27511503). The presence of this variant in one affected homozygote and in combination with a reported pathogenic variant in 2 individuals with MPS increases the likelihood that the p.Pro533Leu variant is pathogenic (VariationID: 11909; PMID: 9787109, 27511503; doi: 10.7124/bc.00093B). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PM3, PM1, PM2_supporting, PP3 (Richards 2015). -

not provided Pathogenic:1 Other:1

not provided, no classification provided	clinical testing	GeneDx	-	The P533R variant in the IDUA gene has been reported previously in the homozygous state or in the heterozygous state with a presumed second IDUA variant in individuals with MPS I (Alif et al., 1999; Laradi et al., 2005; Fahiminiya et al., 2014). The P533R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P533R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies of P533R indicate that this variant leads to a 50% reduction in the enzymatic rate of IDUA and confers lower thermodynamic stability compared to wild type protein (Bie et al., 2013). A missense variant in the same residue, P533L, has been previously identified in the heterozygous state with a second IDUA variant in two individuals with MPS I (Voskoboeva et al., 1998). Therefore, we interpret P533R as a pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;.
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.0	D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.68
MVP		0.99
MPC		0.76
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.86
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121965021; hg19: chr4-997206;