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

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: May 20, 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:: RCV002463371.6

Allele description [Variation Report for NM_016219.5(MAN1B1):c.1075G>T (p.Gly359Ter)]

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

Gene:

MAN1B1:mannosidase alpha class 1B member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.3

Genomic location:

Preferred name:

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

HGVS:

NC_000009.12:g.137101493G>T
NG_031978.1:g.19567G>T
NM_016219.5:c.1075G>TMANE SELECT
NP_057303.2:p.Gly359Ter
NC_000009.11:g.139995945G>T
NM_016219.4:c.1075G>T
NR_045720.2:n.1090G>T
NR_045721.2:n.1221G>T

Protein change:

G359*

Molecular consequence:

NR_045720.2:n.1090G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_045721.2:n.1221G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_016219.5:c.1075G>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Rafiq syndrome (RAFQS)
Identifiers:: MONDO: MONDO:0013624; MedGen: C3280127; Orphanet: 88616; OMIM: 614202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002525507	Service de Biologie Medicale, CIUSSS du Saguenay-Lac-Saint-Jean	no assertion criteria provided	Pathogenic (Aug 11, 2017)	inherited	clinical testing
SCV004329767	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24566669, 28492532
SCV005397689	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (May 20, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24566669, 36786328, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002525507

Service de Biologie Medicale, CIUSSS du Saguenay-Lac-Saint-Jean

no assertion criteria provided

Pathogenic
(Aug 11, 2017)

inherited

clinical testing

SCV004329767

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 3, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005397689

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(May 20, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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	inherited	yes	5	2	not provided	not provided	yes	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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency.

Van Scherpenzeel M, Timal S, Rymen D, Hoischen A, Wuhrer M, Hipgrave-Ederveen A, Grunewald S, Peanne R, Saada A, Edvardson S, Grønborg S, Ruijter G, Kattentidt-Mouravieva A, Brum JM, Freckmann ML, Tomkins S, Jalan A, Prochazkova D, Ondruskova N, Hansikova H, Willemsen MA, Hensbergen PJ, et al.

Brain. 2014 Apr;137(Pt 4):1030-8. doi: 10.1093/brain/awu019. Epub 2014 Feb 24.

PubMed [citation]

PMID:: 24566669

See all PubMed Citations (4)

Details of each submission

From Service de Biologie Medicale, CIUSSS du Saguenay-Lac-Saint-Jean, SCV002525507.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	yes	clinical testing (GTR000518112.3)	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided	(GTR000518112.3)	5	not provided	2	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004329767.1

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

Description

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).

#	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 Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center, SCV005397689.1

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

Description

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

#	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

Last Updated: Nov 18, 2024

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