NM_000528.4(MAN2B1):c.685C>T (p.Arg229Trp) AND Deficiency of alpha-mannosidase

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Dec 28, 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:: RCV000206936.11

Allele description [Variation Report for NM_000528.4(MAN2B1):c.685C>T (p.Arg229Trp)]

NM_000528.4(MAN2B1):c.685C>T (p.Arg229Trp)

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.685C>T (p.Arg229Trp)

HGVS:

NC_000019.10:g.12663781G>A
NG_008318.1:g.7997C>T
NG_015814.1:g.1978G>A
NM_000528.4:c.685C>TMANE SELECT
NM_001173498.2:c.685C>T
NP_000519.2:p.Arg229Trp
NP_001166969.1:p.Arg229Trp
NC_000019.9:g.12774595G>A
NM_000528.3:c.685C>T
O00754:p.Arg229Trp

Protein change:

R229W

Links:

UniProtKB: O00754#VAR_068042; dbSNP: rs763257568

NCBI 1000 Genomes Browser:

rs763257568

Molecular consequence:

NM_000528.4:c.685C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001173498.2:c.685C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000243964	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no assertion criteria provided	Uncertain significance (Jun 7, 2012)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000800761	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (May 10, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11959458, 22161967, 21505070 Citation Link,
SCV001225168	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 28, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26048034, 11959458, 22161967, 28492532
SCV002014509	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]
SCV002511544	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 14, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22161967, 21505070, 11959458, 34614013 Citation Link,
SCV002526386	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 10, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11959458, 26048034, 22161967, 21505070, 25741868
SCV004191843	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 22, 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	yes	1	not provided	not provided	not provided	not provided	clinical testing, literature only
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
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.

Mkaouar R, Riahi Z, Charfeddine C, Chelly I, Boudabbous H, Dallali H, Bonnet C, Hechmi M, Bekri S, Zitouna N, Zekri L, Tounsi A, Kefi R, Marrakchi J, Messaoud O, Kraoua I, Maalej S, Turki Ben Youssef I, Ben Hmid A, Giraudet F, Bouchoucha S, Tebib N, et al.

PLoS One. 2021;16(10):e0258202. doi: 10.1371/journal.pone.0258202.

PubMed [citation]

PMID:: 34614013
PMCID:: PMC8494324

See all PubMed Citations (7)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000243964.1

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

From Counsyl, SCV000800761.1

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

#	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 Invitae, SCV001225168.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 229 of the MAN2B1 protein (p.Arg229Trp). This variant is present in population databases (rs763257568, gnomAD 0.007%). This missense change has been observed in individual(s) with mannosidosis (PMID: 22161967, 26048034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208258). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAN2B1 protein function. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 11959458, 22161967). 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, SCV002014509.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511544.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: MAN2B1 c.685C>T (p.Arg229Trp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 38, N-terminal domain (IPR000602) 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 1.6e-05 in 251450 control chromosomes (gnomAD). c.685C>T has been reported in the literature in multiple individuals affected with Alpha-Mannosidosis (Rise Stensland_2012, Mkaouar_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Berg_2002, Rise Stensland_2012, Mkaouar_2021). Three ClinVar submitters (evaluation after 2014) cite 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 DASA, SCV002526386.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

The c.685C>T;p.(Arg229Trp) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 208258; PMID: 26048034; 22161967; 11959458; 21505070) - PS4_moderate.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11959458) - PS3_moderate. The variant is present at low allele frequencies population databases (rs763257568– gnomAD 0.0001314%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg229Trp) was detected in trans with a Pathogenic variant (PMID: 26048034) - PM3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic

#	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 Baylor Genetics, SCV004191843.1

#	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

Relating variation to medicine