4-1004286-C-G

Position:

• chr4-1004286-C-G

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.1855C>G​(p.Arg619Gly) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 0.378

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]

IDUA (HGNC:):

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, 0.972
• PP5: Variant 4-1004286-C-G is Pathogenic according to our data. Variant chr4-1004286-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11924.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.1855C>G	p.Arg619Gly	missense_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.1855C>G	p.Arg619Gly	missense_variant	14/14	2	NM_000203.5	ENSP00000425081.2
IDUA	ENST00000247933.9	c.1855C>G	p.Arg619Gly	missense_variant	14/14	1		ENSP00000247933.4
IDUA	ENST00000514698.5	n.1966C>G		non_coding_transcript_exon_variant	11/11	5
IDUA	ENST00000652070.1	n.1911C>G		non_coding_transcript_exon_variant	13/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 619 of the IDUA protein (p.Arg619Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Hurler–Scheie syndrome (PMID: 10466419, 12189649). ClinVar contains an entry for this variant (Variation ID: 11924). 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. Experimental studies have shown that this missense change affects IDUA function (PMID: 10466419, 12189649). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2024	Variant summary: IDUA c.1855C>G (p.Arg619Gly) results in a non-conservative amino acid change located in the Alpha-L-iduronidase, C-terminal domain (IPR049167) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247950 control chromosomes (gnomAD). c.1855C>G has been reported in the literature in at least one individual affected with Mucopolysaccharidosis Type 1 (Lee-Chen_1999). These data indicate that the variant may 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 (Lee-Chen_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10466419, 12189649, 15521993, 24480078, 15300847). ClinVar contains an entry for this variant (Variation ID: 11924). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Mucopolysaccharidosis, MPS-I-H/S Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1999

- -

Hurler syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Apr 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.92
MVP		0.93
MPC		0.86
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.81
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121965031; hg19: chr4-998074;