IDUA p.Ala327Pro

Variant names:

• chr4-1002275-G-C
• rs199801029
• NM_000203.5:c.979G>C
• IDUA p.Ala327Pro

Your query was ambiguous. Multiple possible variants found:

• chr4-1002275-G-C
• chr4-1002275-GCG-CCT
• chr4-1002275-GCG-CCC
• chr4-1002275-GCG-CCA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PP3_Moderate PP5_Very_Strong

The NM_000203.5(IDUA):​c.979G>C​(p.Ala327Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,610,950 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001425318: "functional analysis in patient cells support that c.979G>C results in reduced IDUA ensymatic activity."" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A327A) has been classified as Likely benign. The gene IDUA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 0.419
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women's Health
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001425318: "functional analysis in patient cells support that c.979G>C results in reduced IDUA ensymatic activity."; SCV000695977: Functional studies found very low enzymatic residual activity in homozygote and compound heterozygote MPS I patients (Oussorena__2013, Yogalingam_2004).; SCV000834627: Experimental studies have shown that this missense change affects IDUA function (PMID: 15300847, 23786846).; SCV000929873: Low in vivo enzymatic activity in homozygote. PM2: Very low frequency in GnomAD no
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000203.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 4-1002275-G-C is Pathogenic according to our data. Variant chr4-1002275-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 167190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.979G>C	p.Ala327Pro	missense	Exon 8 of 14	NP_000194.2	P35475-1
	IDUA	NM_001363576.1		c.583G>C	p.Ala195Pro	missense	Exon 7 of 13	NP_001350505.1
	IDUA	NR_110313.1		n.1067G>C		non_coding_transcript_exon	Exon 8 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.979G>C	p.Ala327Pro	missense	Exon 8 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.979G>C	p.Ala327Pro	missense	Exon 8 of 14	ENSP00000247933.4	P35475-1
	IDUA	ENST00000962389.1		c.1054G>C	p.Ala352Pro	missense	Exon 9 of 15	ENSP00000632448.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000660 AC: 16 AN: 242572 AF XY: 0.0000606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000143 AC: 209 AN: 1458728 Hom.: 0 Cov.: 35 AF XY: 0.000128 AC XY: 93 AN XY: 725556

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.0000673 AC: 3 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000184 AC: 204 AN: 1110938

Other (OTH) AF: 0.0000332 AC: 2 AN: 60280

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152222 Hom.: 0 Cov.: 34 AF XY: 0.0000807 AC XY: 6 AN XY: 74362

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000453

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Mucopolysaccharidosis type 1 (7)
6	-	-	not provided (6)
2	-	-	Hurler syndrome (2)
1	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.42
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.69
Sift	Benign	0.22	T
Sift4G	Benign	0.18	T
Varity_R		0.67
gMVP		0.90
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199801029;

hg19: chr4-996063;