rs794727896

Positions:

• chr4-1002459-C-A
• chr4-1002459-C-G
• chr4-1002459-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000203.5(IDUA):​c.1163C>A​(p.Thr388Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,401,078 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T388T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 5.91

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 4-1002459-C-A is Pathogenic according to our data. Variant chr4-1002459-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198696.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1163C>A	p.Thr388Lys	missense_variant	8/14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.1163C>A	p.Thr388Lys	missense_variant	8/14	2	NM_000203.5	ENSP00000425081	P1
IDUA	ENST00000247933.9	c.1163C>A	p.Thr388Lys	missense_variant	8/14	1		ENSP00000247933	P1
IDUA	ENST00000514698.5	n.1270C>A		non_coding_transcript_exon_variant	5/11	5
IDUA	ENST00000652070.1	n.1219C>A		non_coding_transcript_exon_variant	7/13

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000651 AC: 1 AN: 153708 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000911

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: 0.00000143 AC: 2 AN: 1401078 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 691618

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

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 13, 2020	The p.Thr388Lys variant in IDUA has been reported in 1 individual with mucopolysaccharidosis (MPS) (PMID: 27520059) and has been identified in 0.009% (1/10974) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs794727896). 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 has also been reported in ClinVar (VariationID: 198686) as a VUS by Counsyl and as likely pathogenic by EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Thr388Arg, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 28752568, 21963080, 28728811; Variation ID: 496834). The presence of this variant in 1 affected homozygote with MPS increases the likelihood that the p.Thr388Lys variant is pathogenic (PMID: 27520059). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PP3, PM3_supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 388 of the IDUA protein (p.Thr388Lys). This variant is present in population databases (rs794727896, gnomAD 0.01%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 27520059, 31194252). ClinVar contains an entry for this variant (Variation ID: 198696). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. This variant disrupts the p.Thr388 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14516901, 17606547, 21253827, 21963080, 28752568). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 21, 2024	Variant summary: IDUA c.1163C>A (p.Thr388Lys) results in a non-conservative amino acid change located in the glycosyl hydrolases family 39, N-terminal catalytic domain (IPR049166) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-06 in 153708 control chromosomes (gnomAD). c.1163C>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (example: Clarke_2019, Kwak_2016). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1163C>G, p.Thr388Arg), supporting the critical relevance of codon 388 to IDUA protein function. The following publications have been ascertained in the context of this evaluation (PMID: 31194252, 27520059). ClinVar contains an entry for this variant (Variation ID: 198696). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 20, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 22, 2016	- -

Hurler syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.88
MVP		0.99
MPC		0.83
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.80

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: rs794727896; hg19: chr4-996247;