NM_000203.5(IDUA):c.1225G>C (p.Gly409Arg) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Mar 7, 2022
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:: RCV000078375.19

Allele description [Variation Report for NM_000203.5(IDUA):c.1225G>C (p.Gly409Arg)]

NM_000203.5(IDUA):c.1225G>C (p.Gly409Arg)

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.1225G>C (p.Gly409Arg)

HGVS:

NC_000004.12:g.1002767G>C
NG_008103.1:g.20771G>C
NM_000203.4(IDUA):c.1225G>C
NM_000203.5:c.1225G>CMANE SELECT
NM_001363576.1:c.829G>C
NP_000194.2:p.Gly409Arg
NP_000194.2:p.Gly409Arg
NP_001350505.1:p.Gly277Arg
LRG_1277t1:c.1225G>C
LRG_1277:g.20771G>C
LRG_1277p1:p.Gly409Arg
NC_000004.11:g.996555G>C
NM_000203.3:c.1225G>C
NM_000203.4(IDUA):c.1225G>C
NM_000203.4:c.1225G>C
NM_000203.5:c.1225G>C
NR_110313.1:n.1313G>C
P35475:p.Gly409Arg

Protein change:

G277R; GLY409ARG

Links:

UniProtKB: P35475#VAR_003370; OMIM: 252800.0005; dbSNP: rs11934801

NCBI 1000 Genomes Browser:

rs11934801

Molecular consequence:

NM_000203.5:c.1225G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363576.1:c.829G>C - missense variant - [Sequence Ontology: SO:0001583]
NR_110313.1:n.1313G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000110221	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Benign (Mar 9, 2015)	germline	clinical testing	Citation Link,
SCV000257642	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Uncertain significance (Jun 8, 2015)	unknown	clinical testing	DGD_Variant_Analysis_Guidelines.docx, Citation Link,
SCV001928974	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV002500155	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Mar 7, 2022)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	7	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Eurofins Ntd Llc (ga), SCV000110221.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	not provided

#	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		7	not provided	not provided	not provided

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000257642.2

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

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

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001928974.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002500155.1

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

Description

Variant summary: IDUA c.1225G>C (p.Gly409Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 118354 control chromosomes (gnomAD), predominantly at a frequency of 0.057 within the African or African-American subpopulation in the gnomAD database, including 16 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Nine ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, three as likely benign, and four as benign. Based on the evidence outlined above, the variant was classified as benign.

#	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: Oct 20, 2024

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