rs747981483

Variant names:

• chr4-987886-C-T
• rs747981483
• NM_000203.5:c.236C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3_Supporting PP4_Moderate PM3 PM2_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The NM_000203.5(IDUA):c.236C>T variant in IDUA is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 79(p.Ala79Val). At least 1 patient with this variant had documented IDUA deficiency within the affected range in leukocytes, urinary GAGs elevation above normal range, and clinical features specific to MPS I including hepatosplenomegaly, arthropathy, and corneal involvement (PP4). This variant has been detected in at least 11 individuals with MPS I. Of those individuals, 2were compound heterozygous, phase not confirmed, for the variant and a variant in IDUA that has been classified as likely pathogenic by the ClinGen LD VCEP (variants: c.1882C>T (p.Arg628Ter) (ClinVar Variation ID: 550421), and c.1402+1G>T) (ClinVar Variation ID: 1323099) (2 x 0.25 points = 0.5 points). Another six individuals are compound heterozygous for the variant and a variant in IDUA, either c.536C>G (p.Thr179Arg) (ClinVar Variation ID: 556358), c.589G>A ((p.Val197Ile) (ClinVar Variation ID: 2720835), c.265C>T (p.Arg89Trp) (ClinVar Variation ID: 580286), c.1877G>A (p.Trp626Ter) (ClinVar Variation ID: 928997), or c.1037T>G (p.Leu346Arg) (ClinVar Variation ID: 11927) (PMIDs: 27520059, 21480867). The allelic data from these individuals will be used in the assessment of the second variant. Three individuals were homozygous for the variant (1 point; PMID:21480867) (PM3). Total 1.5 points (PM3) This variant is absent in gnomAD v4.1.0 (PM2_Supporting). Expression of the variant in CHO-cells resulted in less than 0.1% wild type IDUA activity indicating that this variant may impact protein function (PMID:15300847)(PS3_Supporting). The computational predictor REVEL gives a score of 0.738 which is in the range 0.644-0.773, evidence that correlates with impact to IDUA function at the supporting level (Pejaver et al.) (PP3). Another missense variant c.235G>A (p.Ala79Thr) in the same codon has not yet been reported in a patient with MPS I. Additionally, this other variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LD VCEP (PM5 not met). There is a ClinVar entry for this variant (Variation ID: 1458769). In summary, this variant meets the criteria to be classified as likely pathogenic for MPS I based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 1.0.0): PP4, PM3, PM2_Supporting, PS3_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/CA356987/MONDO:0001586/091

• Frequency: Genomes: not found (cov: 33)
• Consequence: IDUA ENST00000514224.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 4.58
• Publications: 8 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]

SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]

SLC26A1 Gene-Disease associations (from GenCC):

• nephrolithiasis susceptibility caused by SLC26A1

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000514224.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.236C>T	p.Ala79Val	missense	Exon 2 of 14	NP_000194.2
	SLC26A1	NM_022042.4	MANE Select	c.*947G>A		3_prime_UTR	Exon 3 of 3	NP_071325.2
	IDUA	NR_110313.1		n.324C>T		non_coding_transcript_exon	Exon 2 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.236C>T	p.Ala79Val	missense	Exon 2 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.236C>T	p.Ala79Val	missense	Exon 2 of 14	ENSP00000247933.4
	SLC26A1	ENST00000398516.3	TSL:1 MANE Select	c.*947G>A		3_prime_UTR	Exon 3 of 3	ENSP00000381528.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238030 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000554

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Mucopolysaccharidosis type 1 (3)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.013	D
Polyphen		0.98	D
Vest4		0.87
MutPred		0.86		Gain of sheet (P = 0.0477)
MVP		0.98
MPC		0.72
ClinPred		0.93	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.90
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs747981483; hg19: chr4-981674;