NM_000202.8(IDS):c.121_123del (p.Leu41del) AND Mucopolysaccharidosis, MPS-II

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jun 7, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001375841.4

Allele description [Variation Report for NM_000202.8(IDS):c.121_123del (p.Leu41del)]

NM_000202.8(IDS):c.121_123del (p.Leu41del)

Gene:

IDS:iduronate 2-sulfatase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_000202.8(IDS):c.121_123del (p.Leu41del)

HGVS:

NC_000023.11:g.149504274_149504276del
NG_011900.3:g.6059_6061del
NM_000202.8:c.121_123delMANE SELECT
NM_001166550.4:c.-106_-104del
NM_006123.5:c.121_123del
NP_000193.1:p.Leu41del
NP_006114.1:p.Leu41del
NC_000023.10:g.148585804_148585806del
NM_000202.8:c.121_123delCTCMANE SELECT
NR_104128.2:n.290_292del

Protein change:

L41del

Links:

dbSNP: rs2124066296

NCBI 1000 Genomes Browser:

rs2124066296

Molecular consequence:

NM_001166550.4:c.-106_-104del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000202.8:c.121_123del - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_006123.5:c.121_123del - inframe_deletion - [Sequence Ontology: SO:0001822]
NR_104128.2:n.290_292del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Mucopolysaccharidosis, MPS-II (MPS2)
Synonyms:: Mucopolysaccharidosis type II; Attenuated MPS (subtype; formerly known as mild MPS II); Severe MPS II; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010674; MedGen: C0026705; Orphanet: 580; OMIM: 309900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001572613	Pediatrics, All India Institute of Medical Sciences, New Delhi	no assertion criteria provided	Likely pathogenic (May 1, 2014)	germline	research
SCV004048019	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005089166	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 7, 2024)	germline	literature only	PubMed (10) [See all records that cite these PMIDs] 35144014, 27883178, 35005816, 12655569, 27246110, 33676511, 21291454, 30639582, 36945845, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001572613

Pediatrics, All India Institute of Medical Sciences, New Delhi

no assertion criteria provided

Likely pathogenic
(May 1, 2014)

germline

research

SCV004048019

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005089166

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 7, 2024)

germline

literature only

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	10	not provided	not provided	not provided	not provided	clinical testing, literature only
INDIAN	germline	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Genotype-phenotype spectrum of 130 unrelated Indian families with Mucopolysaccharidosis type II.

Agrawal N, Verma G, Saxena D, Kabra M, Gupta N, Mandal K, Moirangthem A, Sheth J, Puri RD, Bijarnia-Mahay S, Kapoor S, Danda S, H SV, Datar CA, Ranganath P, Shukla A, Dalal A, Srivastava P, Devi RR, Phadke SR.

Eur J Med Genet. 2022 Mar;65(3):104447. doi: 10.1016/j.ejmg.2022.104447. Epub 2022 Feb 8.

PubMed [citation]

PMID:: 35144014

Genotype-phenotype correlation in 44 Czech, Slovak, Croatian and Serbian patients with mucopolysaccharidosis type II.

Dvorakova L, Vlaskova H, Sarajlija A, Ramadza DP, Poupetova H, Hruba E, Hlavata A, Bzduch V, Peskova K, Storkanova G, Kecman B, Djordjevic M, Baric I, Fumic K, Barisic I, Reboun M, Kulhanek J, Zeman J, Magner M.

Clin Genet. 2017 May;91(5):787-796. doi: 10.1111/cge.12927. Epub 2017 Mar 17.

PubMed [citation]

PMID:: 27883178

See all PubMed Citations (10)

Details of each submission

From Pediatrics, All India Institute of Medical Sciences, New Delhi, SCV001572613.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	INDIAN	1	not provided	not provided	research	not provided

Description

The variant c.121_123delCTC (p.L41del) was found to be a small in-frame deletion, where the peptide sequence gets shortened by an aliphatic nonpolar neutral amino acid, Leucine at 41 position. It was detected in the hemizygous condition in one of the patients with sever MPS-2 phenotype from Uttarpradesh state of India.

Description

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048019.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The inframe deletion variant p.R4Q in LIPA (NM_000235.4) in IDS gene has been submitted to ClinVar as Likely Pathogenic, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Leu41del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This p.Leu41del causes deletion of amino acid Leucine at position 41. Since this inframe deletion/insertion is not expected to cause protein truncation, the above variant has been classified as Variant of Uncertain Significance (VUS).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV005089166.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	literature only	PubMed (10)

Description

Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Moderate), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Protein length changes in a nonrepeat region or stop–loss variants (PM4_Strong), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		10	not provided	not provided	not provided

Last Updated: Aug 4, 2024

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