NM_000199.5(SGSH):c.1105G>A (p.Glu369Lys) AND Mucopolysaccharidosis, MPS-III-A

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Oct 17, 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:: RCV000005424.24

Allele description [Variation Report for NM_000199.5(SGSH):c.1105G>A (p.Glu369Lys)]

NM_000199.5(SGSH):c.1105G>A (p.Glu369Lys)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000199.5(SGSH):c.1105G>A (p.Glu369Lys)

HGVS:

NC_000017.11:g.80210856C>T
NG_008229.1:g.14545G>A
NG_032778.1:g.45865C>T
NM_000199.5:c.1105G>AMANE SELECT
NM_001352921.3:c.*192G>A
NM_001352922.2:c.*155G>A
NP_000190.1:p.Glu369Lys
NP_000190.1:p.Glu369Lys
LRG_1330:g.45865C>T
NC_000017.10:g.78184655C>T
NM_000199.3:c.1105G>A
NR_148201.2:n.1019G>A
P51688:p.Glu369Lys

Protein change:

E369K; GLU369LYS

Links:

UniProtKB: P51688#VAR_007417; OMIM: 605270.0009; dbSNP: rs104894640

NCBI 1000 Genomes Browser:

rs104894640

Molecular consequence:

NM_001352921.3:c.*192G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001352922.2:c.*155G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000199.5:c.1105G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_148201.2:n.1019G>A - 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
SCV000025606	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2003)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000790783	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (May 2, 2017)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21204211, 22976768, 12702166, 21061399, 10727844, 9554748 Citation Link,
SCV002015101	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 28, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21204211, 9554748, 21061399, 10727844 Citation Link,
SCV002045489	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002153863	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 9, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9554748, 12702166, 10727844, 28492532
SCV004201075	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 17, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations.

Pollard LM, Jones JR, Wood TC.

J Inherit Metab Dis. 2013 Mar;36(2):179-87. doi: 10.1007/s10545-012-9533-7. Epub 2012 Sep 14.

PubMed [citation]

PMID:: 22976768

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 (8)

Details of each submission

From OMIM, SCV000025606.3

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

Description

In 2 second cousins from a large family, Di Natale et al. (2003) showed that mucopolysaccharidosis type IIIA (MPS3A; 252900) was caused by compound heterozygosity for 2 mutations in the SGSH gene: in 1 cousin, with severe disease, the mutations were glu369 to lys (E369K) and arg433 to gln (R433Q; 605270.0010); in the other, with the attenuated form of the disease, the mutations were E369K and pro128 to leu (P128L; 605270.0011). Di Natale et al. (2003) identified R433Q as a severe mutation underlying Sanfilippo syndrome A.

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

From Counsyl, SCV000790783.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002015101.1

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

Description

Variant summary: SGSH c.1105G>A (p.Glu369Lys) results in a 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 4e-06 in 250408 control chromosomes (gnomAD). c.1105G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (e.g. Di Natale_1998, Esposito_2000, Valstar_2010, Heron_2011). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant considerably decreases or abolishes enzyme activity (Esposito_2000, Heron_2011). Two ClinVar submitters (evaluation after 2014) cite 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

From Genome-Nilou Lab, SCV002045489.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002153863.3

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

Description

ClinVar contains an entry for this variant (Variation ID: 5117). This missense change has been observed in individual(s) with Sanfilippo syndrome (PMID: 9554748, 10727844, 12702166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894640, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 369 of the SGSH protein (p.Glu369Lys). 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) performed at Invitae indicates that this missense variant is expected to disrupt SGSH protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844).

#	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 Baylor Genetics, SCV004201075.1

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

#	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

Last Updated: Jul 15, 2024

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