rs121965020

Variant names:

• chr4-987858-C-T
• rs121965020
• NM_000203.5:c.208C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.208C>T (p.Gln70Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 2 of a total of 14 exons, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. An immunochemical assay performed in fibroblast lines from two individuals homozygous for the variant and three individuals compound heterozygous for the variant and p.Trp402Ter found no detectable IDUA protein (PMID:1301941) (PVS1). This variant is the second most common variant identified in patients with mucopolysacchararidosis type 1 (MPS1), and is present mainly in Northern Europe, including Norway (54% of MPS1 alleles), Russia (42% of MPS1 alleles), Poland (30% of MPS1 alleles), and Austria (31% of MPS1 alleles) (Reviewed in PMID:29393969). At least 14 homozygotes (max 0.5 x 2 points = 1 point) and at least 45 individuals who are compound heterozygous for the variant and a second variant in IDUA, including another well-known pathogenic variant, c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908), have been reported (PMID:1301941, 7951228, 11735025, 28752568). The allelic data for many of these patients will be used in the classification of the second variant and is not included here to avoid circular logic. Therefore, only 1 point was awarded here, the maximum points for homozygotes (PM3). Patients meeting two of the requirements for PP4, IDUA deficiency and elevated urine GAG levels have been reported (PMID:1301941) (PP4). The highest population minor allele frequency in gnomAD v4.1.0 is 0.002123 in the Finnish population, followed by 0.0005348 in the European non-Finnish population. This is higher than the Lysosomal Diseases VCEP's threshold for PM2_Supporting (<0.00025) and lower than the threshold for BS1 (>0.0025). Therefore, no population codes are met. More data is available in the literature but the classification of pathogenic has already been reached. There is a ClinVar entry for this variant (Variation ID: 11909). In summary, c.208C>T (p.Gln70Ter) is the second most frequent variant identified in patients with MPS1 and meets the criteria to be classified as pathogenic for this condition. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PVS1, PM3, PP4.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 2, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA204563/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:33 O:1
• Conservation: PhyloP100: 3.66
• Publications: 100 publications found

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]

SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]

SLC26A1 Gene-Disease associations (from GenCC):

• nephrolithiasis susceptibility caused by SLC26A1

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.208C>T	p.Gln70*	stop_gained	Exon 2 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_022042.4	MANE Select	c.*975G>A		3_prime_UTR	Exon 3 of 3	NP_071325.2
	SLC26A1	NM_213613.4		c.*975G>A		3_prime_UTR	Exon 4 of 4	NP_998778.1	Q9H2B4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.208C>T	p.Gln70*	stop_gained	Exon 2 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.208C>T	p.Gln70*	stop_gained	Exon 2 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398516.3	TSL:1 MANE Select	c.*975G>A		3_prime_UTR	Exon 3 of 3	ENSP00000381528.2	Q9H2B4-1

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000472 AC: 115 AN: 243460 AF XY: 0.000513

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00178

Gnomad NFE exome AF: 0.000698

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000481 AC: 703 AN: 1460164 Hom.: 0 Cov.: 30 AF XY: 0.000480 AC XY: 349 AN XY: 726374

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00210 AC: 109 AN: 52006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000522 AC: 580 AN: 1111830

Other (OTH) AF: 0.000182 AC: 11 AN: 60360

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.000592 AC XY: 44 AN XY: 74350

African (AFR) AF: 0.0000724 AC: 3 AN: 41450

American (AMR) AF: 0.000589 AC: 9 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68034

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000436 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000604 AC: 73

EpiCase AF: 0.000491

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
12	-	-	not provided (12)
8	-	-	Mucopolysaccharidosis type 1 (9)
4	-	-	Hurler syndrome (4)
2	-	-	Mucopolysaccharidosis, MPS-I-H/S (2)
2	-	-	Mucopolysaccharidosis, MPS-I-S (2)
2	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (2)
1	-	-	IDUA-related disorder (1)
1	-	-	Interstitial pneumonitis (1)
1	-	-	Mucopolysaccharidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.71	D
PhyloP100		3.7
Vest4		0.84
ClinPred		0.67	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121965020; hg19: chr4-981646;