rs398123260

Variant names:

• chr4-987118-GCGCTCCTGGCCT-G
• rs398123260
• NM_000203.5:c.46_57delTCGCTCCTGGCC

Your query was ambiguous. Multiple possible variants found:

• chr4-987118-GCGCTCCTGGCCT-G
• chr4-987118-GCGCTCCTGGCCT-GCGCTCCTGGCCTCGCTCCTGGCCT

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3_Supporting PM4 PM3 PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.46_57del variant results in an inframe deletion of 4 amino acids (p.Ser16_Ala19del) within the lysosomal signal sequence of IDUA (PM4). This variant is named "134del12" in older literature. At least twelve patients with with variant and a diagnosis of mucopolysaccharidosis type 1 have been reported in the literature. This includes four patients with documented laboratory values showing deficiency of IDUA activity in fibroblasts or leukocytes (PMID:15300847, 21394825, 23786846) one of whom also had documented clinical features consistent with the diagnosis including corneal clouding, joint stiffness, digital contractures, cardiac valve disease, airway obstruction, and developmental delay (PMID:15300847) (PP4). Four individuals have been reported who are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP including two confirmed in trans - c.1750C>T (p.Gln584Ter) (PMID:12189649) and p.Trp402Ter (PMID:11735025); and two phase unknown - c.208C>T (p.Gln70Ter) (PMID:21394825) and c.386-2A>G (PMID:11735025). In addition, at least two homozygotes have been reported PMID:7951228, 21394825) (PM3_VeryStrong). Additional patients are compound heterozygous for the variant and c.603C>G (p.Tyr201Ter) (PMID:21394825), c.1189+5G>A (PMID:21394825); c.1960T>C (p.Ter654ArgextTer*62) (PMID:21394825), c.1049A>T (p.Asn350Ile) (PMID:12559846) and c.1598C>G (p.Pro533Arg) (PMID:15300847). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. When expressed in COS-7 cells, the variant (labeled as "134del12") resulted in 124.6% of normal activity. A 77-kDa precursor protein was observed on Western blot, compared with a major mature 63-kDa form and a minor 77-kDa precursor in cells transfected with wild-type cDNA. These results suggested that the variant prevents correct posttranslational processing and transport to the lysosome (PMID:12189649) (PS3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00006251 (69/1103836 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 92643). In summary, this variant meets the criteria to be classified as pathogenic for mucopolysaccharidosis type 1. IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 1.0.0): PM3_Very Strong, PM4, PP4, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA220509/MONDO:0001586/091

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 36)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: IDUA NM_000203.5 conservative_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 0.445
• Publications: 5 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]

DGKQ (HGNC:2856): (diacylglycerol kinase theta) The protein encoded by this gene contains three cysteine-rich domains, a proline-rich region, and a pleckstrin homology domain with an overlapping Ras-associating domain. It is localized in the speckle domains of the nucleus, and mediates the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.46_57delTCGCTCCTGGCC	p.Ser16_Ala19del	conservative_inframe_deletion	Exon 1 of 14	NP_000194.2
	IDUA	NR_110313.1		n.134_145delTCGCTCCTGGCC		non_coding_transcript_exon	Exon 1 of 14
	SLC26A1	NM_134425.4		c.576+3998_576+4009delAGGCCAGGAGCG		intron	N/A	NP_602297.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.46_57delTCGCTCCTGGCC	p.Ser16_Ala19del	conservative_inframe_deletion	Exon 1 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.46_57delTCGCTCCTGGCC	p.Ser16_Ala19del	conservative_inframe_deletion	Exon 1 of 14	ENSP00000247933.4
	SLC26A1	ENST00000398520.6	TSL:1	c.576+3998_576+4009delAGGCCAGGAGCG		intron	N/A	ENSP00000381532.2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152036 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000495 AC: 64 AN: 1293482 Hom.: 0 AF XY: 0.0000596 AC XY: 38 AN XY: 637434

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000384 AC: 1 AN: 26032

American (AMR) AF: 0.00 AC: 0 AN: 23966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21684

East Asian (EAS) AF: 0.0000362 AC: 1 AN: 27636

South Asian (SAS) AF: 0.00 AC: 0 AN: 69064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3754

European-Non Finnish (NFE) AF: 0.0000589 AC: 61 AN: 1035854

Other (OTH) AF: 0.0000188 AC: 1 AN: 53158

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152036 Hom.: 0 Cov.: 36 AF XY: 0.0000269 AC XY: 2 AN XY: 74276

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Mucopolysaccharidosis type 1 (5)
3	-	-	not provided (3)
1	-	-	Hurler syndrome (1)
1	-	-	IDUA-related disorder (1)
1	-	-	Mucopolysaccharidosis, MPS-I-S (1)
1	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
Mutation Taster		=36/164	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs398123260; hg19: chr4-980906;