rs187833337

chr4-1004041-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000203.5(IDUA):c.1757C>T(p.Ser586Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,612,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S586S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 0.781

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29683197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.1757C>T	p.Ser586Phe	missense_variant	13/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.1757C>T	p.Ser586Phe	missense_variant	13/14	2	NM_000203.5	P1
IDUA	ENST00000247933.9	c.1757C>T	p.Ser586Phe	missense_variant	13/14	1		P1
IDUA	ENST00000514698.5	n.1868C>T		non_coding_transcript_exon_variant	10/11	5
IDUA	ENST00000652070.1	n.1813C>T		non_coding_transcript_exon_variant	12/13

Frequencies

GnomAD3 genomes AF: 0.000186 AC: 28 AN: 150802 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000513

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251224 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135846

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461366 Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27 AN XY: 726978

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000186 AC: 28 AN: 150920 Hom.: 0 Cov.: 32 AF XY: 0.000149 AC XY: 11 AN XY: 73632

Gnomad4 AFR AF: 0.000512

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000683 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 19, 2022	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 586 of the IDUA protein (p.Ser586Phe). This variant is present in population databases (rs187833337, gnomAD 0.06%). This missense change has been observed in individual(s) with a positive newborn screening result for IDUA-related disease (PMID: 29143201, 30442156, 32432561). ClinVar contains an entry for this variant (Variation ID: 571910). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 21, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	Pseudodeficiency variants -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 07, 2023

Variant summary: IDUA c.1757C>T (p.Ser586Phe) 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 allele was found at a frequency of 7.9e-05 in 254582 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (7.9e-05 vs 0.0027), allowing no conclusion about variant significance. c.1757C>T has been reported in the literature in individuals affected with the Pseudo Mucopolysaccharidosis Type 1 (e.g. Burlina_2017, Polo_2020). These reports do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type 1. At least one publication reports experimental evidence evaluating an impact on protein function: the variant was identified as a pseudodeficiency variant with 18% specific enzyme activity when transfected into HAP1 IDUA-deficient cells, placing it within the range of previously documented pseudodeficiency variants. The following publications have been ascertained in the context of this evaluation (PMID: 29143201, 29140481, 32432561, 29947050, 33198351). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.80	D;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.98	D;.
Vest4		0.57
MVP		0.92
MPC		0.66
ClinPred		0.62	D
GERP RS		3.9
Varity_R		0.79
gMVP		0.93

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: rs187833337; hg19: chr4-997829;