VCV001691271.4 - ClinVar

NM_016219.5(MAN1B1):c.1075G>T (p.Gly359Ter)

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.

(4)

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_016219.5(MAN1B1):c.1075G>T (p.Gly359Ter)

Variation ID: 1691271 Accession: VCV001691271.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.3 9: 137101493 (GRCh38) [ NCBI UCSC ] 9: 139995945 (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	Dec 3, 2022	Nov 17, 2024	May 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_016219.5:c.1075G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057303.2:p.Gly359Ter	nonsense
NR_045720.2:n.1090G>T		non-coding transcript variant
NR_045721.2:n.1221G>T		non-coding transcript variant
NC_000009.12:g.137101493G>T
NC_000009.11:g.139995945G>T
NG_031978.1:g.19567G>T

... more HGVS ... less HGVS

Protein change

G359*

Other names

Canonical SPDI

NC_000009.12:137101492:G:T

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.

Links

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.
MAN1B1		-	-	GRCh38 GRCh37	481	635

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.
Rafiq syndrome	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 20, 2024	RCV002463371.6
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 30, 2024	RCV004779274.1

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 (Jun 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Rafiq syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004329767.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 24566669 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1691271). This variant has not been … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1691271). This variant has not been reported in the literature in individuals affected with MAN1B1-related conditions. This variant is present in population databases (rs745337581, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Gly359*) in the MAN1B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAN1B1 are known to be pathogenic (PMID: 24566669). (less)
Pathogenic (Apr 30, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005389916.1 First in ClinVar: Nov 10, 2024 Last updated: Nov 10, 2024	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36786328) (less)
Likely Pathogenic (May 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rafiq syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397689.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (2) PubMed: 24566669‚ 36786328 Comment: This sequence variant is a single nucleotide substitution (G>T) at position 1075 of the coding sequence of the MAN1B1 gene which changes the Gly359 codon … (more) This sequence variant is a single nucleotide substitution (G>T) at position 1075 of the coding sequence of the MAN1B1 gene which changes the Gly359 codon to an early termination codon. As it occurs in exon 8 of 13, this variant is predicted to generate a non-functional allele through either the expression of a truncated mannosidase alpha class 1B member 1 protein or a loss of MAN1B1 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 1691271) that has been observed in individuals affected by congenital heart disease (PMID 28991257) and MAN1B1-congenital disorder of glycosylation (PMID: 36786328). This variant is present in 40 of 1613728 alleles (0.0025%) in the gnomAD v4.1.0 population dataset. Loss-of-function variants in MAN1B1 are a known mechanism of disease (PMID: 24566669). Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PVS1 (less)
Pathogenic (Aug 11, 2017)	no assertion criteria provided Method: clinical testing	Rafiq syndrome Affected status: yes Allele origin: inherited	Service de Biologie Medicale, CIUSSS du Saguenay-Lac-Saint-Jean Accession: SCV002525507.1 First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 Comment: Observed in 3 individuals in the homozygous state from 2 independant families in the Saguenay-Lac-St-Jean region of Québec, Canada.	Number of individuals with the variant: 5 Clinical Features: Developmental delay (present) , neonatal hypotonia (present) , language delay (present) , clinodactyly (present) , high palate (present) , oval facies (present) , ophtalmoplegia (present) … (more) Developmental delay (present) , neonatal hypotonia (present) , language delay (present) , clinodactyly (present) , high palate (present) , oval facies (present) , ophtalmoplegia (present) , intellectual disability (present) , Obesity (present) , scoliosis (present) , articular hypermobility (present) , pectus excavatum (present) (less) Family history: yes

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1691271). This variant has not been reported in the literature in individuals affected with MAN1B1-related conditions. This variant is present in population databases (rs745337581, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Gly359*) in the MAN1B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAN1B1 are known to be pathogenic (PMID: 24566669).

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36786328)

Comment:

This sequence variant is a single nucleotide substitution (G>T) at position 1075 of the coding sequence of the MAN1B1 gene which changes the Gly359 codon to an early termination codon. As it occurs in exon 8 of 13, this variant is predicted to generate a non-functional allele through either the expression of a truncated mannosidase alpha class 1B member 1 protein or a loss of MAN1B1 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar 1691271) that has been observed in individuals affected by congenital heart disease (PMID 28991257) and MAN1B1-congenital disorder of glycosylation (PMID: 36786328). This variant is present in 40 of 1613728 alleles (0.0025%) in the gnomAD v4.1.0 population dataset. Loss-of-function variants in MAN1B1 are a known mechanism of disease (PMID: 24566669). Based upon the evidence, we consider this variant to be likely pathogenic. ACMG Criteria: PM2, PVS1

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
Portrait of autosomal recessive diseases in the French-Canadian founder population of Saguenay-Lac-Saint-Jean.	Cruz Marino T	American journal of medical genetics. Part A	2023	PMID: 36786328
Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency.	Van Scherpenzeel M	Brain : a journal of neurology	2014	PMID: 24566669

Text-mined citations for this variant ...

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_016219.5(MAN1B1):c.1075G>T (p.Gly359Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...