VCV000161412.20 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 161412 Accession: VCV000161412.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q33.1 5: 150541651 (GRCh38) [ NCBI UCSC ] 5: 149921213 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 9, 2016	Oct 20, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001543.5:c.1831G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001534.1:p.Gly611Ser	missense
NM_001301063.2:c.1831G>A	NP_001287992.1:p.Gly611Ser	missense
NC_000005.10:g.150541651G>A
NC_000005.9:g.149921213G>A
NG_041806.1:g.48874G>A
	P52848:p.Gly611Ser

... more HGVS ... less HGVS

Protein change

G611S

Other names

Canonical SPDI

NC_000005.10:150541650:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA174008 UniProtKB: P52848#VAR_072646 OMIM: 600853.0004 dbSNP: rs606231459 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NDST1		-	-	GRCh38 GRCh37	-	-

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Intellectual disability, autosomal recessive 46	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Nov 2, 2023	RCV000148928.18
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV002279948.15
Global developmental delay	Likely pathogenic (1)	criteria provided, single submitter	Feb 16, 2022	RCV002463649.1
See cases	Likely pathogenic (1)	criteria provided, single submitter	Oct 20, 2022	RCV003128390.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV002568838.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022
Likely pathogenic (Feb 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Global developmental delay Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV002758631.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: ACMG criteria used to clasify this variant: PS4, PM1, PM2_SUP, PP3
Likely pathogenic (May 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal recessive 46 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003814499.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Nov 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal recessive 46 Affected status: yes Allele origin: germline	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV005016493.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024
Pathogenic (Dec 03, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Mental retardation, autosomal recessive 46 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001467757.1 First in ClinVar: Jan 07, 2021 Last updated: Jan 07, 2021	Publications: PubMed (3) PubMed: 27870114‚ 27620904‚ 25125150 Comment: 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 … (more) 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. (less)
Likely pathogenic (Mar 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal recessive 46 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581582.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4_MOD, PM3, PM1_SUP, PM2_SUP, PP3	Number of individuals with the variant: 1 Sex: male
Likely pathogenic (Jun 21, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003935846.1 First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25125150, 31589614, 27870114, 27620904, 35887114) (less)
Likely pathogenic (Oct 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV003804820.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG categories: PM2,PM3,PP3,PP5 Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) Age: 10-19 years Sex: male Tissue: blood
Likely pathogenic (Mar 23, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003439241.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 25125150‚ 27620904 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 NDST1 protein function. ClinVar contains an entry for this variant (Variation ID: 161412). This missense change has been observed in individuals with clinical features of intellectual disability (PMID: 25125150, 27620904; Invitae). This variant is present in population databases (rs606231459, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 611 of the NDST1 protein (p.Gly611Ser). (less)
Likely pathogenic (Dec 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004701944.8 First in ClinVar: Mar 10, 2024 Last updated: Oct 20, 2024	Comment: NDST1: PM1, PM2, PM3, PP3 Number of individuals with the variant: 3
Pathogenic (Nov 01, 2014)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 46 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000195816.5 First in ClinVar: Dec 07, 2014 Last updated: Apr 11, 2022	Publications: PubMed (1) PubMed: 25125150 Comment on evidence: 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 … (more) 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. (less)
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Comment:

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.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25125150, 31589614, 27870114, 27620904, 35887114)

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 NDST1 protein function. ClinVar contains an entry for this variant (Variation ID: 161412). This missense change has been observed in individuals with clinical features of intellectual disability (PMID: 25125150, 27620904; Invitae). This variant is present in population databases (rs606231459, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 611 of the NDST1 protein (p.Gly611Ser).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.	Martínez F	Journal of medical genetics	2017	PMID: 27620904
The Molecular Genetics of Autosomal Recessive Nonsyndromic Intellectual Disability: a Mutational Continuum and Future Recommendations.	Khan MA	Annals of human genetics	2016	PMID: 27870114
NDST1 missense mutations in autosomal recessive intellectual disability.	Reuter MS	American journal of medical genetics. Part A	2014	PMID: 25125150

Text-mined citations for rs606231459 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs606231459 ...