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NM_003896.4(ST3GAL5):c.584G>C (p.Cys195Ser) AND GM3 synthase deficiency

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Oct 12, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000240853.3

Allele description [Variation Report for NM_003896.4(ST3GAL5):c.584G>C (p.Cys195Ser)]

NM_003896.4(ST3GAL5):c.584G>C (p.Cys195Ser)

Gene:
ST3GAL5:ST3 beta-galactoside alpha-2,3-sialyltransferase 5 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p11.2
Genomic location:
Preferred name:
NM_003896.4(ST3GAL5):c.584G>C (p.Cys195Ser)
HGVS:
  • NC_000002.12:g.85847939C>G
  • NG_012807.1:g.46096G>C
  • NM_001042437.2:c.515G>C
  • NM_001354223.2:c.200G>C
  • NM_001354224.2:c.200G>C
  • NM_001354226.2:c.200G>C
  • NM_001354227.2:c.500G>C
  • NM_001354229.2:c.500G>C
  • NM_001354233.2:c.200G>C
  • NM_001354234.1:c.200G>C
  • NM_001354238.1:c.500G>C
  • NM_001354247.1:c.-321G>C
  • NM_001354248.1:c.200G>C
  • NM_001363847.1:c.584G>C
  • NM_003896.4:c.584G>CMANE SELECT
  • NP_001035902.1:p.Cys172Ser
  • NP_001341152.1:p.Cys67Ser
  • NP_001341153.1:p.Cys67Ser
  • NP_001341155.1:p.Cys67Ser
  • NP_001341156.1:p.Cys167Ser
  • NP_001341158.1:p.Cys167Ser
  • NP_001341162.1:p.Cys67Ser
  • NP_001341163.1:p.Cys67Ser
  • NP_001341167.1:p.Cys167Ser
  • NP_001341177.1:p.Cys67Ser
  • NP_001350776.1:p.Cys195Ser
  • NP_003887.3:p.Cys195Ser
  • NC_000002.11:g.86075062C>G
  • NM_003896.3:c.584G>C
Protein change:
C167S; CYS195SER
Links:
OMIM: 604402.0003; dbSNP: rs886037930
NCBI 1000 Genomes Browser:
rs886037930
Molecular consequence:
  • NM_001354247.1:c.-321G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001042437.2:c.515G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354223.2:c.200G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354224.2:c.200G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354226.2:c.200G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354227.2:c.500G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354229.2:c.500G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354233.2:c.200G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354234.1:c.200G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354238.1:c.500G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354248.1:c.200G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001363847.1:c.584G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003896.4:c.584G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
GM3 synthase deficiency (SPDRS)
Synonyms:
SALT AND PEPPER MENTAL RETARDATION SYNDROME; Salt and pepper developmental regression syndrome; Salt and pepper syndrome
Identifiers:
MONDO: MONDO:0018274; MedGen: C1836824; Orphanet: 171714; OMIM: 609056

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000299338OMIM
no assertion criteria provided
Pathogenic
(Sep 16, 2016) 		germlineliterature only

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

SCV004282470Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 12, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome-like phenotype.

Lee JS, Yoo Y, Lim BC, Kim KJ, Song J, Choi M, Chae JH.

Am J Med Genet A. 2016 Aug;170(8):2200-5. doi: 10.1002/ajmg.a.37773. Epub 2016 May 27.

PubMed [citation]
PMID:
27232954

Total loss of GM3 synthase activity by a normally processed enzyme in a novel variant and in all ST3GAL5 variants reported to cause a distinct congenital disorder of glycosylation.

Indellicato R, Parini R, Domenighini R, Malagolini N, Iascone M, Gasperini S, Masera N, dall'Olio F, Trinchera M.

Glycobiology. 2019 Mar 1;29(3):229-241. doi: 10.1093/glycob/cwy112.

PubMed [citation]
PMID:
30576498
See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000299338.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 2 Korean sisters with salt and pepper developmental regression syndrome (SPDRS; 609056), Lee et al. (2016) identified compound heterozygous missense mutations in the ST3GAL5 gene: a c.584G-C transversion (c.584G-C, NM_003896), resulting in a cys195-to-ser (C195S) substitution, and a c.601G-A transition, resulting in a gly201-to-arg (G201R; 604402.0004) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The C195S variant was not found in the 1000 Genomes Project or ExAC databases, whereas the G201R variant was found at a low frequency (8.3 x 10(-6)). Both mutations occurred at highly conserved residues in the L-motif of the protein. Plasma gangliosides in the 2 sibs were barely detectable, suggesting a loss of function. Functional studies of the variants and measurement of enzyme activity in patient cell were not performed.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004282470.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 195 of the ST3GAL5 protein (p.Cys195Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GM synthetase deficiency (PMID: 27232954). 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. ClinVar contains an entry for this variant (Variation ID: 254245). 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 ST3GAL5 protein function. Experimental studies have shown that this missense change affects ST3GAL5 function (PMID: 30576498). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024