rs781136336

chr4-1003397-T-Cchr4-1003397-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000203.5(IDUA):c.1577T>C(p.Leu526Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,522,386 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. L526L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 1.82

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857
• PP5: Variant 4-1003397-T-C is Pathogenic according to our data. Variant chr4-1003397-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567566.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=1, Uncertain_significance=1}. Variant chr4-1003397-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IDUA	NM_000203.5	c.1577T>C	p.Leu526Pro	missense_variant	11/14	ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.1577T>C	p.Leu526Pro	missense_variant	11/14	2	NM_000203.5	P1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151922 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000336 AC: 40 AN: 118962 Hom.: 0 AF XY: 0.000397 AC XY: 26 AN XY: 65432

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: 0.000708

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000566

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000404 AC: 554 AN: 1370464 Hom.: 0 Cov.: 33 AF XY: 0.000413 AC XY: 279 AN XY: 676024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000575

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000526

Gnomad4 FIN exome AF: 0.0000299

Gnomad4 NFE exome AF: 0.000460

Gnomad4 OTH exome AF: 0.000280

GnomAD4 genome AF: 0.000270 AC: 41 AN: 151922 Hom.: 0 Cov.: 33 AF XY: 0.000337 AC XY: 25 AN XY: 74204

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000728 Hom.: 0

Bravo AF: 0.000234

ExAC AF: 0.000179 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2023	Variant summary: IDUA c.1577T>C (p.Leu526Pro) results in a non-conservative amino acid change in 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 0.00034 in 118962 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.00034 vs 0.0027), allowing no conclusion about variant significance. c.1577T>C has been reported in the literature in newborn screening studies (e.g. Donati_2018, Wasserstein_2019, Polo_2020, Bosfield_2021). One newborn in particular was found to be homozygous for this variant and exhibited urinary and dried blood spot glycosaminoglycan (GAG) levels within normal range (Donati_2018, Polo_2020). However, no follow-up data from a later stage of life were available to determine the actual phenotype. In contrast, a second homozygous individual was reported who had a clinical diagnosis of Mucopolysaccharidosis Type 1 with an attenuated phenotype (Zhang_2022). Importantly, the variant was also detected in combination with other known pathogenic variants in individuals affected with Mucopolysaccharidosis Type 1 (Pollard_2013, Dickson_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33098355, 31194252, 26260077, 30442156, 22976768, 32432561, 30093709, 35787971). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=1)/likely pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 526 of the IDUA protein (p.Leu526Pro). This variant is present in population databases (rs781136336, gnomAD 0.07%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 22976768, 30442156; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 567566). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2021	Observed in apparent homozygous state through newborn screening in an infant with >50% enzymatic activity (Donati et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33072983, 32432561, 33147872, 27535533, 30442156, 22976768, 26260077, 30093709) -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Jan 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.59	T;.
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.85
MVP		0.99
MPC		0.97
ClinPred		0.26	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.98

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: rs781136336; hg19: chr4-997185;