rs786200915

Positions:

• chr4-1001700-C-CCTGCT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000203.5(IDUA):​c.613_617dup​(p.Glu207AlafsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,448,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: IDUA NM_000203.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: -1.02

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-1001700-C-CCTGCT is Pathogenic according to our data. Variant chr4-1001700-C-CCTGCT is described in ClinVar as [Pathogenic]. Clinvar id is 11921.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.613_617dup	p.Glu207AlafsTer29	frameshift_variant	6/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.613_617dup	p.Glu207AlafsTer29	frameshift_variant	6/14	2	NM_000203.5	ENSP00000425081	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000869 AC: 2 AN: 230064 Hom.: 0 AF XY: 0.00000789 AC XY: 1 AN XY: 126694

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

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: 0.00000622 AC: 9 AN: 1448012 Hom.: 0 Cov.: 34 AF XY: 0.00000555 AC XY: 4 AN XY: 720748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2018	Variant summary: IDUA c.613_617dupTGCTC (p.Glu207AlafsX29) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.8e-06 in 227460 control chromosomes (gnomAD). The variant, c.613_617dupTGCTC, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (Ghosh_2017, Kwak_2016, Yamagishi_1996). 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 (Kwak_2016). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant in Japan -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 10, 2020	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The p.Glu207AlafsTer29 variant in IDUA has been reported in least 7 individuals with mucopolysaccharidosis (MPS) (PMID: 8664897, 27520059) and has been identified in 0.011% (2/17752) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs786200915). 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 is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 207 and leads to a premature termination codon 29 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in 2 affected homozygotes and in combination with a reported pathogenic variant in at least 3 individuals with MPS increases the likelihood that the p.Glu207AlafsTer29 variant is pathogenic (VariationID: 11922; PMID: 8664897). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that the variant will cause loss of function and the presence of the variant in combination with known pathogenic variants in individuals with MPS. ACMG/AMP Criteria applied: PVS1, PM3_strong, PM2_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 31, 2023	This variant is also known as 704ins5. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11921). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (PMID: 8664897, 27520059, 29620724). This variant is present in population databases (rs786200915, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Glu207Alafs*29) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). -

Hurler syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 27, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2004	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs786200915; hg19: chr4-995488;