4-1004027-C-G

Position:

• chr4-1004027-C-G

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.1743C>G​(p.Tyr581Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,088 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -1.53

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 4-1004027-C-G is Pathogenic according to our data. Variant chr4-1004027-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550883.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.1743C>G	p.Tyr581Ter	stop_gained	13/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1743C>G	p.Tyr581Ter	stop_gained	13/14	2	NM_000203.5	ENSP00000425081	P1
IDUA	ENST00000247933.9	c.1743C>G	p.Tyr581Ter	stop_gained	13/14	1		ENSP00000247933	P1
IDUA	ENST00000514698.5	n.1854C>G		non_coding_transcript_exon_variant	10/11	5
IDUA	ENST00000652070.1	n.1799C>G		non_coding_transcript_exon_variant	12/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251162 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461088 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 28, 2023	This sequence change creates a premature translational stop signal (p.Tyr581*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 550883). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 21394825, 27196898). This variant is present in population databases (rs776787370, gnomAD 0.02%). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 11, 2021	Variant summary: IDUA c.1743C>G (p.Tyr581X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251162 control chromosomes (gnomAD). c.1743C>G has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (e.g. Souillet_2003, Chkioua_2011, Tebani_2016, Guffon_2021). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2021	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 73 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 21394825, 27196898, 9672523, 21521498, 21639919, 32432561, 33072983, 33147872, 30442156, 25525159) -

Hurler syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.018	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.61
GERP RS		-5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs776787370; hg19: chr4-997815;