NM_000199.5(SGSH):c.1297C>T (p.Arg433Trp) AND Mucopolysaccharidosis, MPS-III-A

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Dec 11, 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:: RCV000665964.15

Allele description [Variation Report for NM_000199.5(SGSH):c.1297C>T (p.Arg433Trp)]

NM_000199.5(SGSH):c.1297C>T (p.Arg433Trp)

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.1297C>T (p.Arg433Trp)

HGVS:

NC_000017.11:g.80210664G>A
NG_008229.1:g.14737C>T
NG_032778.1:g.45673G>A
NM_000199.5:c.1297C>TMANE SELECT
NM_001352921.3:c.*384C>T
NM_001352922.2:c.*347C>T
NP_000190.1:p.Arg433Trp
LRG_1330:g.45673G>A
NC_000017.10:g.78184463G>A
NM_000199.3:c.1297C>T
NR_148201.2:n.1211C>T

Protein change:

R433W

Links:

dbSNP: rs777267343

NCBI 1000 Genomes Browser:

rs777267343

Molecular consequence:

NM_001352921.3:c.*384C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001352922.2:c.*347C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000199.5:c.1297C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148201.2:n.1211C>T - 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

Recent activity

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Drosophila willistoni isolate 14030-0811.24, whole genome shotgun sequencing pro...
Drosophila willistoni isolate 14030-0811.24, whole genome shotgun sequencing project
gi|2053590485|gb|JAFEWB000000000.1| B010000000

Nucleotide
Mus musculus synergin, gamma (Synrg), transcript variant 4, mRNA
Mus musculus synergin, gamma (Synrg), transcript variant 4, mRNA
gi|2227679165|ref|NM_001405115.1|

Nucleotide
synergin gamma isoform 5 [Mus musculus]
synergin gamma isoform 5 [Mus musculus]
gi|2227679069|ref|NP_001392045.1|

Protein
Mus musculus synergin, gamma (Synrg), transcript variant 8, mRNA
Mus musculus synergin, gamma (Synrg), transcript variant 8, mRNA
gi|2227679243|ref|NM_001405121.1|

Nucleotide
PREDICTED: Homo sapiens guanylate cyclase 1 soluble subunit alpha 1 (GUCY1A1), t...
PREDICTED: Homo sapiens guanylate cyclase 1 soluble subunit alpha 1 (GUCY1A1), transcript variant X3, mRNA
gi|2462596818|ref|XM_054349842.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000790185	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Mar 17, 2017)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21204211, 11182930, 15542396, 15146460, 11343308 Citation Link,
SCV000893480	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 17, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000957485	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11182930, 29023963, 15542396, 28492532
SCV001361816	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 5, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22976768, 11343308, 21204211, 15146460, 11182930, 15542396 Citation Link,
SCV002045483	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]
SCV004201112	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 18, 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	unknown	unknown	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

Citations

PubMed

Prediction of phenotypic severity in mucopolysaccharidosis type IIIA.

Knottnerus SJG, Nijmeijer SCM, IJlst L, Te Brinke H, van Vlies N, Wijburg FA.

Ann Neurol. 2017 Nov;82(5):686-696. doi: 10.1002/ana.25069. Epub 2017 Oct 26.

PubMed [citation]

PMID:: 29023963
PMCID:: PMC5725696

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

See all PubMed Citations (9)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Counsyl, SCV000790185.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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 Fulgent Genetics, Fulgent Genetics, SCV000893480.2

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000957485.6

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 433 of the SGSH protein (p.Arg433Trp). This variant is present in population databases (rs777267343, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 11182930, 15542396, 29023963). ClinVar contains an entry for this variant (Variation ID: 551014). 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 SGSH protein function. Experimental studies have shown that this missense change affects SGSH function (PMID: 15542396). 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, SCV001361816.1

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

Description

Variant summary: SGSH c.1297C>T (p.Arg433Trp) results in a non-conservative amino acid change located in a domain of unknown function, DUF4976 (IPR032506) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250408 control chromosomes (gnomAD). The variant, c.1297C>T, has been reported in the literature in homozygosity or in compound heterozygous state in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (e.g. Beesley_2000, Chabas_2001, Heron_2011, Pollard_2013). These data indicate that the variant is very likely to be associated with disease. Publications reported no significant sulfamidase activity in fibroblasts from a homozygous patient (Montfort_2004), and in transiently transfected mammalian cells (Muschol_2004). Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic (1x) and pathogenic (1x). 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, SCV002045483.1

#	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 Baylor Genetics, SCV004201112.1

#	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: Oct 8, 2024

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