rs747981483

Positions:

• chr4-987886-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000203.5(IDUA):​c.236C>T​(p.Ala79Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 4-987886-C-T is Pathogenic according to our data. Variant chr4-987886-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1458769.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDUA	ENST00000514224.2	c.236C>T	p.Ala79Val	missense_variant	2/14	2	NM_000203.5	P1
SLC26A1	ENST00000398516.3	c.*947G>A		3_prime_UTR_variant	3/3	1	NM_022042.4	P1

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

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. -

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
MutationTaster	Benign	1.0	D;N;D;D
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;