chr4-1004292-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3PM2

This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1861C>G variant in IDUA is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 621 (p.Arg621Gly). This variant is absent in gnomAD v2.0 (PM2_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002483 (293/1179952 alleles) in the European non-Finnish population, which is less than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) (PM2 Supporting). The computational predictor REVEL gives a score of 0.733 which is in the range 0.644-0.773, evidence that correlates with the impact on IDUA function at the supporting level (PP3).There is a ClinVar entry for this variant (Variation ID: 444626). In summary, this variant meets the criteria to be classified as uncertain significance for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0): PM2 Supporting, PP3.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2802458/MONDO:0001586/091

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

IDUA
NM_000203.5 missense

Scores

6
10
3

Clinical Significance

Uncertain significance reviewed by expert panel U:9

Conservation

PhyloP100: 1.51
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IDUANM_000203.5 linkc.1861C>G p.Arg621Gly missense_variant Exon 14 of 14 ENST00000514224.2 NP_000194.2 P35475-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IDUAENST00000514224.2 linkc.1861C>G p.Arg621Gly missense_variant Exon 14 of 14 2 NM_000203.5 ENSP00000425081.2 P35475-1
IDUAENST00000247933.9 linkc.1861C>G p.Arg621Gly missense_variant Exon 14 of 14 1 ENSP00000247933.4 P35475-1
IDUAENST00000514698.5 linkn.1972C>G non_coding_transcript_exon_variant Exon 11 of 11 5
IDUAENST00000652070.1 linkn.1917C>G non_coding_transcript_exon_variant Exon 13 of 13

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
151964
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000278
AC:
69
AN:
248290
Hom.:
1
AF XY:
0.000274
AC XY:
37
AN XY:
134874
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000198
Gnomad NFE exome
AF:
0.000552
Gnomad OTH exome
AF:
0.000492
GnomAD4 exome
AF:
0.000206
AC:
301
AN:
1458874
Hom.:
1
Cov.:
32
AF XY:
0.000204
AC XY:
148
AN XY:
725874
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
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:
0.000158
Gnomad4 NFE exome
AF:
0.000251
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
151964
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74210
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000283
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000244
Hom.:
0
Bravo
AF:
0.000178
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000453
AC:
55
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1 Uncertain:4
Sep 16, 2020
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dec 06, 2024
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel
Significance: Uncertain significance
Review Status: reviewed by expert panel
Collection Method: curation

The NM_000203.5:c.1861C>G variant in IDUA is a missense variant predicted to cause the substitution of arginine by glycine at amino acid 621 (p.Arg621Gly). This variant is absent in gnomAD v2.0 (PM2_Supporting). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0002483 (293/1179952 alleles) in the European non-Finnish population, which is less than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) (PM2 Supporting). The computational predictor REVEL gives a score of 0.733 which is in the range 0.644-0.773, evidence that correlates with the impact on IDUA function at the supporting level (PP3). There is a ClinVar entry for this variant (Variation ID: 444626). In summary, this variant meets the criteria to be classified as uncertain significance for MPS I based on the IDUA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 1.0): PM2 Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on December 6, 2024). -

Oct 24, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 621 of the IDUA protein (p.Arg621Gly). This variant is present in population databases (rs121965025, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. 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: 444626). 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. 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. -

not provided Uncertain:4
Mar 28, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2 -

Sep 20, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 01, 2017
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 16, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Listed in one table of a publication as being seen heterozygous with unknown phase with a pathogenic variant in a patient with severe MPS I, but is unclear if this may represent a typographical error as this variant is not listed in the other two tables summarizing the identified variants but a nonsense variant at the same nucleotide position is listed (Voskoboeva et al., 2021); Has not otherwise been published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35141277, 34833038, 33301762, 27896125) -

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Uncertain:1
Jan 04, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Uncertain
0.080
D
BayesDel_noAF
Pathogenic
0.23
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
D;.
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
0.013
D
MutationAssessor
Uncertain
2.7
M;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-4.3
D;D
REVEL
Pathogenic
0.73
Sift
Benign
0.042
D;D
Sift4G
Uncertain
0.037
D;D
Polyphen
0.93
P;.
Vest4
0.84
MVP
0.90
MPC
0.70
ClinPred
0.33
T
GERP RS
4.7
Varity_R
0.67
gMVP
0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121965025; hg19: chr4-998080; API