chr4-987886-C-T

Position:

• chr4-987886-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3 PP3 PM2_Supporting PS3_Supporting PP4_Moderate

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 NM_000203.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 4.58

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]

IDUA (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.236C>T	p.Ala79Val	missense_variant	2/14	ENST00000514224.2	NP_000194.2
SLC26A1	NM_022042.4	c.*947G>A		3_prime_UTR_variant	3/3	ENST00000398516.3	NP_071325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.236C>T	p.Ala79Val	missense_variant	2/14	2	NM_000203.5	ENSP00000425081.2
SLC26A1	ENST00000398516	c.*947G>A		3_prime_UTR_variant	3/3	1	NM_022042.4	ENSP00000381528.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000420 AC: 1 AN: 238030 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129756

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 SAS exome AF: 0.00

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

Bravo AF: 0.0000189

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 08, 2022	Experimental studies have shown that this missense change affects IDUA function (PMID: 12189649). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 1458769). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 15300847, 21462124, 21734815). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 79 of the IDUA protein (p.Ala79Val). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 23, 2024	Variant summary: IDUA c.236C>T (p.Ala79Val) results in a non-conservative amino acid change located in the Glycosyl hydrolases family 39, N-terminal catalytic domain (IPR049166) 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 4.2e-06 in 238030 control chromosomes. c.236C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type 1 (e.g. Wang_2012, Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 28752568, 21480867). ClinVar contains an entry for this variant (Variation ID: 1458769). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Dec 06, 2024	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, 2 were 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) -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs747981483; hg19: chr4-981674;