NM_000528.4(MAN2B1):c.1109G>A (p.Trp370Ter) AND Deficiency of alpha-mannosidase

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jan 6, 2024
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:: RCV000169531.12

Allele description [Variation Report for NM_000528.4(MAN2B1):c.1109G>A (p.Trp370Ter)]

NM_000528.4(MAN2B1):c.1109G>A (p.Trp370Ter)

Gene:

MAN2B1:mannosidase alpha class 2B member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.13

Genomic location:

Preferred name:

NM_000528.4(MAN2B1):c.1109G>A (p.Trp370Ter)

HGVS:

NC_000019.10:g.12658428C>T
NG_008318.1:g.13350G>A
NM_000528.4:c.1109G>AMANE SELECT
NM_001173498.2:c.1106G>A
NP_000519.2:p.Trp370Ter
NP_001166969.1:p.Trp369Ter
NC_000019.9:g.12769242C>T
NM_000528.3:c.1109G>A

Protein change:

W369*

Links:

dbSNP: rs786204715

NCBI 1000 Genomes Browser:

rs786204715

Molecular consequence:

NM_000528.4:c.1109G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001173498.2:c.1106G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Deficiency of alpha-mannosidase (MANSA)
Synonyms:: Lysosomal alpha-D-mannosidase deficiency; Alpha mannosidase B deficiency; Mannosidosis, alpha B lysosomal; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009561; MedGen: C0024748; Orphanet: 61; OMIM: 248500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000221010	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jan 8, 2015)	unknown	literature only	PubMed (1) [See all records that cite this PMID] Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001337781	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001581392	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 6, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9915946, 22161967, 28492532
SCV002014453	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002086937	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 10, 2021)	germline	clinical testing
SCV004191913	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2022)	unknown	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	unknown	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, literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spectrum of mutations in alpha-mannosidosis.

Berg T, Riise HM, Hansen GM, Malm D, Tranebjaerg L, Tollersrud OK, Nilssen O.

Am J Hum Genet. 1999 Jan;64(1):77-88.

PubMed [citation]

PMID:: 9915946
PMCID:: PMC1377705

Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations.

Riise Stensland HM, Klenow HB, Van Nguyen L, Hansen GM, Malm D, Nilssen Ø.

Hum Mutat. 2012 Mar;33(3):511-20. doi: 10.1002/humu.22005. Epub 2012 Jan 23. Erratum in: Hum Mutat. 2016 Aug;37(8):827.

PubMed [citation]

PMID:: 22161967

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000221010.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001337781.2

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

Description

Variant summary: MAN2B1 c.1109G>A (p.Trp370X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. This variant also falls at the last nucleotide of exon 8 of the MAN2B1 coding sequence, which is part of the consensus splice site for this exon. Two computational tools predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251334 control chromosomes (gnomAD). The variant, c.1109G>A, has been reported in the literature in two homozygous patients (siblings) affected with Alpha-Mannosidosis (Riise Stensland_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/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 Invitae, SCV001581392.4

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

Description

This sequence change creates a premature translational stop signal (p.Trp370*) in the MAN2B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mannosidosis (PMID: 22161967). ClinVar contains an entry for this variant (Variation ID: 189118). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Genome-Nilou Lab, SCV002014453.1

#	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 Natera, Inc., SCV002086937.1

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

#	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 Baylor Genetics, SCV004191913.1

#	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: Feb 20, 2024

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