4-1004329-C-G

Variant names:

• chr4-1004329-C-G
• rs886043347
• NM_000203.5:c.1898C>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000203.5(IDUA):​c.1898C>G​(p.Ser633Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,632 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.17

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 4-1004329-C-G is Pathogenic according to our data. Variant chr4-1004329-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 286242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1898C>G	p.Ser633Trp	missense_variant	Exon 14 of 14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1898C>G	p.Ser633Trp	missense_variant	Exon 14 of 14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1898C>G	p.Ser633Trp	missense_variant	Exon 14 of 14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.2009C>G		non_coding_transcript_exon_variant	Exon 11 of 11	5
IDUA	ENST00000652070.1	n.1954C>G		non_coding_transcript_exon_variant	Exon 13 of 13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249054 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459632 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Feb 10, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11735025, 24480078, 24798265, 32235807, 33389473) -

Mucopolysaccharidosis type 1 Pathogenic:2

Jul 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 633 of the IDUA protein (p.Ser633Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 24798265, 33389473). ClinVar contains an entry for this variant (Variation ID: 286242). 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.Ser633 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11735025, 16438163, 21480867, 26825088, 27146977). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 22, 2020

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Ser633Trp variant in IDUA has been reported in at least 4 individuals with mucopolysaccharidosis (MPS) (PMID: 24798265; doi: 10.1016/j.ymgme.2015.12.397) and has been identified in 0.003% (1/34546) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886043347). 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 as pathogenic by EGL Genetic Diagnostics (Variation ID: 286242). 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.Ser633Leu, has been reported pathogenic in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 16438163, 28752568, 11735025, 2448007; VariationID: 556406). The p.Ser633Trp variant is located in a region of IDUA that is important for protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 24480078). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS based on a-L-Iduronidase activity being <1% of normal, consistent with disease (PMID: 24798265; doi: 10.1016/j.ymgme.2015.12.397). The presence of this variant in at least 3 affected homozygotes and in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Ser633Trp variant is pathogenic (VariationID: 11908; PMID: 24798265; doi: 10.1016/j.ymgme.2015.12.397). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PM3, PP3, PM1_supporting, PP4 (Richards 2015). -

Inborn genetic diseases Pathogenic:1

Mar 12, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.86
MVP		0.97
MPC		0.89
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.86
gMVP		0.99

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: rs886043347; hg19: chr4-998117;