NM_001379228.1(MRAP):c.106+1del AND Glucocorticoid deficiency 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 22, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002250648.2

Allele description [Variation Report for NM_001379228.1(MRAP):c.106+1del]

NM_001379228.1(MRAP):c.106+1del

Gene:

MRAP:melanocortin 2 receptor accessory protein [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

21q22.11

Genomic location:

Preferred name:

NM_001379228.1(MRAP):c.106+1del

HGVS:

NC_000021.9:g.32299078del
NG_016234.1:g.12266del
NM_001285394.2:c.-72+5946del
NM_001379228.1:c.106+1delMANE SELECT
NM_178817.4:c.106+1del
NM_206898.2:c.106+1del
NC_000021.8:g.33671389del

Nucleotide change:

IVS3, G DEL, +1

Links:

OMIM: 609196.0004; dbSNP: rs1476574441

NCBI 1000 Genomes Browser:

rs1476574441

Molecular consequence:

NM_001285394.2:c.-72+5946del - intron variant - [Sequence Ontology: SO:0001627]
NM_001379228.1:c.106+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_178817.4:c.106+1del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_206898.2:c.106+1del - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Name:: Glucocorticoid deficiency 2 (GCCD2)
Synonyms:: FAMILIAL GLUCOCORTICOID DEFICIENCY 2
Identifiers:: MONDO: MONDO:0011826; MedGen: C4049714; Orphanet: 361; OMIM: 607398

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022071	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2005)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002521146	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15654338, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000022071

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2005)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002521146

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 22, 2022)

germline

clinical testing

PubMed (2)
[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	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2.

Metherell LA, Chapple JP, Cooray S, David A, Becker C, Rüschendorf F, Naville D, Begeot M, Khoo B, Nürnberg P, Huebner A, Cheetham ME, Clark AJ.

Nat Genet. 2005 Feb;37(2):166-70. Epub 2005 Jan 16.

PubMed [citation]

PMID:: 15654338

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000022071.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 6 individuals from 5 families with glucocorticoid deficiency (607398), Metherell et al. (2005) found deletion of the first nucleotide in the donor site of intron 3 of the MRAP gene (IVS3DS+1delG). This was the second most frequent mutation causing glucocorticoid deficiency unrelated to defect in the MC2R gene (see 202200) in their study.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002521146.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with MRAP related disorder (ClinVar ID: VCV000444068 / PMID: 15654338). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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