rs121965022

Positions:

• chr4-987842-C-A
• chr4-987842-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000203.5(IDUA):​c.192C>A​(p.Tyr64Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,158 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: IDUA NM_000203.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.165

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-987842-C-A is Pathogenic according to our data. Variant chr4-987842-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-987842-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.192C>A	p.Tyr64Ter	stop_gained	2/14	ENST00000514224.2	NP_000194.2
SLC26A1	NM_022042.4	c.*991G>T		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.192C>A	p.Tyr64Ter	stop_gained	2/14	2	NM_000203.5	ENSP00000425081	P1
SLC26A1	ENST00000398516.3	c.*991G>T		3_prime_UTR_variant	3/3	1	NM_022042.4	ENSP00000381528	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460158 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2023	Variant summary: IDUA c.192C>A (p.Tyr64X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 243844 control chromosomes (gnomAD). c.192C>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (example: Bach_1993). These data indicate that the variant may be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 8328452). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 11914). This premature translational stop signal has been observed in individual(s) with clinical features of mucopolysaccharidosis type I (PMID: 8328452). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr64*) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). -

Hurler syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1993	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Uncertain	0.19
Eigen_PC	Benign	-0.077
FATHMM_MKL	Benign	0.23	N
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.79
ClinPred		0.85	D
GERP RS		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121965022; hg19: chr4-981630;