rs1461992821

chr4-1002273-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000203.5(IDUA):c.977T>C(p.Ile326Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44

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 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000203.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.977T>C	p.Ile326Thr	missense_variant	8/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.977T>C	p.Ile326Thr	missense_variant	8/14	2	NM_000203.5	P1
IDUA	ENST00000247933.9	c.977T>C	p.Ile326Thr	missense_variant	8/14	1		P1
IDUA	ENST00000514698.5	n.1084T>C		non_coding_transcript_exon_variant	5/11	5
IDUA	ENST00000652070.1	n.1033T>C		non_coding_transcript_exon_variant	7/13

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 326 of the IDUA protein (p.Ile326Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IDUA-related conditions. ClinVar contains an entry for this variant (Variation ID: 526834). 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) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;.
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	D;.
Vest4		0.78
MVP		0.99
MPC		0.62
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.89

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: rs1461992821; hg19: chr4-996061;