NM_000199.5(SGSH):c.1153del (p.Arg385fs) AND Mucopolysaccharidosis, MPS-III-A

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 2, 2024
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:: RCV001174996.3

Allele description [Variation Report for NM_000199.5(SGSH):c.1153del (p.Arg385fs)]

NM_000199.5(SGSH):c.1153del (p.Arg385fs)

Gene:

SGSH:N-sulfoglucosamine sulfohydrolase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000199.5(SGSH):c.1153del (p.Arg385fs)

HGVS:

NC_000017.11:g.80210809del
NG_008229.1:g.14593del
NG_032778.1:g.45818del
NM_000199.5:c.1153delMANE SELECT
NM_001352921.3:c.*240del
NM_001352922.2:c.*203del
NP_000190.1:p.Arg385fs
LRG_1330:g.45818del
NC_000017.10:g.78184607del
NC_000017.10:g.78184608del
NM_000199.3:c.1153delC
NR_148201.2:n.1067del

Protein change:

R385fs

Links:

dbSNP: rs2041615714

NCBI 1000 Genomes Browser:

rs2041615714

Molecular consequence:

NM_001352921.3:c.*240del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001352922.2:c.*203del - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000199.5:c.1153del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_148201.2:n.1067del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mucopolysaccharidosis, MPS-III-A (MPS3A)
Synonyms:: SULFAMIDASE DEFICIENCY; Mucopoly-saccharidosis type 3A; Sanfilippo syndrome A; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009655; MedGen: C0086647; Orphanet: 581; Orphanet: 79269; OMIM: 252900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001338492	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 2, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003442421	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11668611, 21204211, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001338492

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 2, 2020)

germline

clinical testing

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

Citation Link,

SCV003442421

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 2, 2024)

germline

clinical testing

PubMed (3)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications.

Yogalingam G, Hopwood JJ.

Hum Mutat. 2001 Oct;18(4):264-81. Review.

PubMed [citation]

PMID:: 11668611

Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece.

Héron B, Mikaeloff Y, Froissart R, Caridade G, Maire I, Caillaud C, Levade T, Chabrol B, Feillet F, Ogier H, Valayannopoulos V, Michelakakis H, Zafeiriou D, Lavery L, Wraith E, Danos O, Heard JM, Tardieu M.

Am J Med Genet A. 2011 Jan;155A(1):58-68. doi: 10.1002/ajmg.a.33779.

PubMed [citation]

PMID:: 21204211

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338492.1

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

Description

Variant summary: SGSH c.1153delC (p.Arg385AlafsX28) 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. The variant was absent in 251050 control chromosomes (gnomAD). c.1153delC has been reported in the literature in at least one individual affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A- Yogalingam_2001). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely 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 Invitae, SCV003442421.2

#	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 creates a premature translational stop signal (p.Arg385Alafs*28) in the SGSH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 118 amino acid(s) of the SGSH protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 11668611). This variant is also known as c.1152del. ClinVar contains an entry for this variant (Variation ID: 917772). This variant disrupts a region of the SGSH protein in which other variant(s) (p.Trp479*) have been determined to be pathogenic (PMID: 21204211). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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

Last Updated: Feb 20, 2024

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