NM_000528.4(MAN2B1):c.1383C>A (p.Tyr461Ter) AND Deficiency of alpha-mannosidase

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Dec 19, 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:: RCV000301281.19

Allele description [Variation Report for NM_000528.4(MAN2B1):c.1383C>A (p.Tyr461Ter)]

NM_000528.4(MAN2B1):c.1383C>A (p.Tyr461Ter)

Genes:

LOC129391064:MPRA-validated peak3365 silencer [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.1383C>A (p.Tyr461Ter)

HGVS:

NC_000019.10:g.12657482G>T
NG_008318.1:g.14296C>A
NM_000528.4:c.1383C>AMANE SELECT
NM_001173498.2:c.1380C>A
NP_000519.2:p.Tyr461Ter
NP_001166969.1:p.Tyr460Ter
NC_000019.9:g.12768296G>T
NM_000528.3:c.1383C>A

Protein change:

Y460*

Links:

dbSNP: rs775200333

NCBI 1000 Genomes Browser:

rs775200333

Molecular consequence:

NM_000528.4:c.1383C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001173498.2:c.1380C>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
SCV000410795	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22161967, 26048034 Citation Link,
SCV001468285	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 25, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22161967, 27959697, 26048034 Citation Link,
SCV002014364	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]
SCV002086932	Natera, Inc.	no assertion criteria provided	Pathogenic (May 8, 2020)	germline	clinical testing
SCV002246670	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9915946, 22161967, 28492532
SCV002503619	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 9, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22161967, 26048034, 25741868
SCV004191898	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Citations

PubMed

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.

Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, Walkiewicz M, Bi W, Xiao R, Ding Y, Xia F, Beaudet AL, Muzny DM, Gibbs RA, Boerwinkle E, Eng CM, Sutton VR, Shaw CA, Plon SE, Yang Y, Lupski JR.

N Engl J Med. 2017 Jan 5;376(1):21-31. doi: 10.1056/NEJMoa1516767. Epub 2016 Dec 7.

PubMed [citation]

PMID:: 27959697
PMCID:: PMC5335876

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

See all PubMed Citations (6)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000410795.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The MAN2B1 c.1383C>A (p.Tyr461Ter) variant is a stop-gained variant that has been reported in two studies in which it was found in a total of eight individuals with alpha-mannosidosis (including two sibling pairs) in a compound heterozygous state (Stensland et al 2012; Borgwardt et al. 2015). Control data are not available for this variant, which is reported at a frequency of 0.0001525 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele only in a region of poor sequence coverage. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Tyr461Ter variant is classified as pathogenic for alpha-mannosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001468285.1

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

Description

Variant summary: MAN2B1 c.1383C>A (p.Tyr461X) 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. The variant allele was found at a frequency of 1.7e-05 in 172302 control chromosomes. c.1383C>A has been reported in the literature in individuals affected with Alpha-Mannosidosis and subsequently cited by others (example, 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. Two 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. One submitter cites overlapping evidence utilized in the context of this evaluation. 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 Genome-Nilou Lab, SCV002014364.1

#	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., SCV002086932.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002246670.3

#	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.Tyr461*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with alpha-mannosidosis (PMID: 22161967). ClinVar contains an entry for this variant (Variation ID: 281152). 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 Molecular Genetics, Royal Melbourne Hospital, SCV002503619.2

#	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 termination codon at position 461 in exon 11 (of 24) of MAN2B1 (p.(Tyr461*)). It is expected to result in nonsense mediated decay, in a gene where loss of function is an established mechanism of disease (ClinGen). The variant is present in a large population cohort at a frequency of 0.002% (3/172,302 alleles, 0 homozygotes in gnomAD v2.1), but this is based on three alleles in a region of poor coverage. It has been reported in multiple individuals with alpha-mannosidosis with a second pathogenic allele, and segregates with the condition in at least one family (PMID: 22161967, 26048034). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PP1.

#	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, SCV004191898.1

#	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: Sep 29, 2024

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