NM_000203.5(IDUA):c.623G>A (p.Gly208Asp) AND Mucopolysaccharidosis type 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 2, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001855539.5

Allele description [Variation Report for NM_000203.5(IDUA):c.623G>A (p.Gly208Asp)]

NM_000203.5(IDUA):c.623G>A (p.Gly208Asp)

Gene:

IDUA:alpha-L-iduronidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_000203.5(IDUA):c.623G>A (p.Gly208Asp)

HGVS:

NC_000004.12:g.1001712G>A
NG_008103.1:g.19716G>A
NM_000203.5:c.623G>AMANE SELECT
NM_001363576.1:c.227G>A
NP_000194.2:p.Gly208Asp
NP_001350505.1:p.Gly76Asp
LRG_1277t1:c.623G>A
LRG_1277:g.19716G>A
LRG_1277p1:p.Gly208Asp
NC_000004.11:g.995500G>A
NM_000203.3:c.623G>A
NM_000203.4:c.623G>A
NR_110313.1:n.711G>A

Protein change:

G208D

Links:

dbSNP: rs1430681871

NCBI 1000 Genomes Browser:

rs1430681871

Molecular consequence:

NM_000203.5:c.623G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363576.1:c.227G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_110313.1:n.711G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mucopolysaccharidosis type 1
Synonyms:: Mucopolysaccharidosis type I; MPS 1; Attenuated MPS I (subtype); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0001586; MedGen: C0023786

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002117240	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12509712, 29976218, 28492532
SCV004038278	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12509712, 21480867, 12559846, 29976218 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002117240

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 2, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004038278

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 7, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Diversity of mutations and distribution of single nucleotide polymorphic alleles in the human alpha-L-iduronidase (IDUA) gene.

Li P, Wood T, Thompson JN.

Genet Med. 2002 Nov-Dec;4(6):420-6.

PubMed [citation]

PMID:: 12509712

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002117240.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 208 of the IDUA protein (p.Gly208Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 12509712, 29976218). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 554590). 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. For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004038278.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: IDUA c.623G>A (p.Gly208Asp) results in a non-conservative amino acid change in the encoded protein sequence. This alters a highly conserved residue in which other missense variants (p.Gly208Val, p.Gly208Ala) have been found in association with disease (HGMD, ClinVar). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 227442 control chromosomes (gnomAD). c.623G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (Li_2002, Matte_2003, Wang_2012, Giugliani_2018), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, findind a variant effect that results in <1% of normal enzymatic activity (Matte_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12509712, 12559846, 21480867, 29976218). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 29, 2024

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