NM_001543.5(NDST1):c.1831G>A (p.Gly611Ser) AND Intellectual disability, autosomal recessive 46

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Nov 2, 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:: RCV000148928.18

Allele description [Variation Report for NM_001543.5(NDST1):c.1831G>A (p.Gly611Ser)]

NM_001543.5(NDST1):c.1831G>A (p.Gly611Ser)

Gene:

NDST1:N-deacetylase and N-sulfotransferase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q33.1

Genomic location:

Preferred name:

NM_001543.5(NDST1):c.1831G>A (p.Gly611Ser)

HGVS:

NC_000005.10:g.150541651G>A
NG_041806.1:g.48874G>A
NM_001301063.2:c.1831G>A
NM_001543.5:c.1831G>AMANE SELECT
NP_001287992.1:p.Gly611Ser
NP_001534.1:p.Gly611Ser
NC_000005.9:g.149921213G>A
NM_001543.4:c.1831G>A
P52848:p.Gly611Ser

Protein change:

G611S; GLY611SER

Links:

UniProtKB: P52848#VAR_072646; OMIM: 600853.0004; dbSNP: rs606231459

NCBI 1000 Genomes Browser:

rs606231459

Molecular consequence:

NM_001301063.2:c.1831G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001543.5:c.1831G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Intellectual disability, autosomal recessive 46 (MRT46)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 46
Identifiers:: MONDO: MONDO:0014499; MedGen: C4015283; Orphanet: 88616; OMIM: 616116

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000195816	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2014)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001467757	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 3, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27870114, 27620904, 25125150 Citation Link,
SCV002581582	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003814499	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 16, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005016493	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The Molecular Genetics of Autosomal Recessive Nonsyndromic Intellectual Disability: a Mutational Continuum and Future Recommendations.

Khan MA, Khan S, Windpassinger C, Badar M, Nawaz Z, Mohammad RM.

Ann Hum Genet. 2016 Nov;80(6):342-368. doi: 10.1111/ahg.12176. Review.

PubMed [citation]

PMID:: 27870114

High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.

Martínez F, Caro-Llopis A, Roselló M, Oltra S, Mayo S, Monfort S, Orellana C.

J Med Genet. 2017 Feb;54(2):87-92. doi: 10.1136/jmedgenet-2016-103964. Epub 2016 Sep 12.

PubMed [citation]

PMID:: 27620904

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000195816.5

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

Description

In 2 Turkish sibs (family MZ-778/12) with autosomal recessive intellectual developmental disorder-46 (MRT46; 616116), Reuter et al. (2014) identified a homozygous c.1831G-A transition in the NDST1 gene, resulting in a gly611-to-ser (G611S) substitution at a highly conserved residue near the 3-prime-phosphoadenosine 5-prime-phosphate (PAP)-binding site in the sulfotransferase domain. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases, or in ethnically matched controls. Functional studies of the variant were not performed.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001467757.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: NDST1 c.1831G>A (p.Gly611Ser) results in a non-conservative amino acid change located in the Sulfotransferase domain (IPR000863) 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 8e-06 in 250738 control chromosomes (gnomAD). c.1831G>A has been reported in the literature as a homozygous mutation in multiple individuals affected with intellectual disability (e.g. Reuter_2014, Martinez_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as 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 MGZ Medical Genetics Center, SCV002581582.1

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

From Revvity Omics, Revvity, SCV003814499.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV005016493.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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