chr4-1004320-GC-G

Position:

• chr4-1004320-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000203.5(IDUA):​c.1893del​(p.Phe632SerfsTer?) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.140

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0367 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-1004320-GC-G is Pathogenic according to our data. Variant chr4-1004320-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1004320-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1893del	p.Phe632SerfsTer?	frameshift_variant	14/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1893del	p.Phe632SerfsTer?	frameshift_variant	14/14	2	NM_000203.5	ENSP00000425081	P1
IDUA	ENST00000247933.9	c.1893del	p.Phe632SerfsTer?	frameshift_variant	14/14	1		ENSP00000247933	P1
IDUA	ENST00000514698.5	n.2004del		non_coding_transcript_exon_variant	11/11	5
IDUA	ENST00000652070.1	n.1949del		non_coding_transcript_exon_variant	13/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459510 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726142

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: 0.0000196

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Phe632Serfs variant in IDUA has been reported in at least 2 individuals with mucopolysaccharidosis (MPS) (PMID: 21394825, 29906569) and was absent from large population studies. This variant has been reported in ClinVar (VariationID: 495733) as likely pathogenic by Integrated Genetics. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 632. This termination codon occurs within the the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in an affected homozygote increases the likelihood that the p.Phe632Serfs variant is pathogenic (PMID: 29906569). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_strong, PM2, PM3_supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2020	Variant summary: IDUA c.1893delC (p.Phe632SerfsX77+) causes a frameshift which results in an extension of the protein. The variant was absent in 248970 control chromosomes (gnomAD). c.1893delC has been reported in the literature in individuals (compound heterozygous and homozygous) affected with Hurler syndrome - a severe form of Mucopolysaccharidosis Type 1 (Bertola_2011, Oussoren_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2023	This sequence change results in a frameshift in the IDUA gene (p.Phe632Serfs*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the IDUA protein and extend the protein by an uncertain number of additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with Hurler syndrome (PMID: 21394825). ClinVar contains an entry for this variant (Variation ID: 495733). This variant disrupts a region of the IDUA protein in which other variant(s) (p.Ser633Leu) have been determined to be pathogenic (PMID: 11735025, 16438163, 21480867, 26825088, 27146977). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hurler syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Jul 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs1553917754; hg19: chr4-998108;