4-987915-C-T

Variant names:

• chr4-987915-C-T
• rs754966840
• NM_000203.5:c.265C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000203.5(IDUA):​c.265C>T​(p.Arg89Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,450,156 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000832691: Experimental studies have shown that this missense change affects IDUA function (PMID:14559116)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89Q) has been classified as Pathogenic. The gene IDUA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.936
• Publications: 16 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: AD, AR Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000832691: Experimental studies have shown that this missense change affects IDUA function (PMID: 14559116).; SCV001363955: Functional characterization demonstrated the variant protein was present in a similar- or increased amount in cell lines from patients compared to controls, but had a severely reduced enzymatic activity in both patient derived cell lines and transfected Chinese hamster ovary cells (Bunge_1998, Hein_2003).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-987916-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11922.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 4-987915-C-T is Pathogenic according to our data. Variant chr4-987915-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 580286.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.265C>T	p.Arg89Trp	missense	Exon 2 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_022042.4	MANE Select	c.*918G>A		3_prime_UTR	Exon 3 of 3	NP_071325.2
	SLC26A1	NM_213613.4		c.*918G>A		3_prime_UTR	Exon 4 of 4	NP_998778.1	Q9H2B4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.265C>T	p.Arg89Trp	missense	Exon 2 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.265C>T	p.Arg89Trp	missense	Exon 2 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398516.3	TSL:1 MANE Select	c.*918G>A		3_prime_UTR	Exon 3 of 3	ENSP00000381528.2	Q9H2B4-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000136 AC: 3 AN: 221242 AF XY: 0.0000166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000308

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1450156 Hom.: 0 Cov.: 30 AF XY: 0.00000972 AC XY: 7 AN XY: 720470

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.0000231 AC: 1 AN: 43346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25880

East Asian (EAS) AF: 0.00 AC: 0 AN: 39044

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1107190

Other (OTH) AF: 0.0000500 AC: 3 AN: 59956

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000831 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Mucopolysaccharidosis type 1 (3)
1	-	-	Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.94
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.95		Loss of glycosylation at K86 (P = 0.0815)
MVP		1.0
MPC		0.77
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.87
gMVP		0.97
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs754966840; hg19: chr4-981703;