NM_005912.3(MC4R):c.63_64del (p.Tyr21_Arg22delinsTer) AND Obesity

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Jan 22, 2020)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000582390.2

Allele description [Variation Report for NM_005912.3(MC4R):c.63_64del (p.Tyr21_Arg22delinsTer)]

NM_005912.3(MC4R):c.63_64del (p.Tyr21_Arg22delinsTer)

Gene:
MC4R:melanocortin 4 receptor [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
18q21.32
Genomic location:
Preferred name:
NM_005912.3(MC4R):c.63_64del (p.Tyr21_Arg22delinsTer)
HGVS:
  • NC_000018.10:g.60372287_60372288del
  • NG_016441.1:g.5482_5483del
  • NM_005912.3:c.63_64delMANE SELECT
  • NP_005903.2:p.Tyr21_Arg22delinsTer
  • LRG_1346t1:c.63_64del
  • LRG_1346:g.5482_5483del
  • LRG_1346p1:p.Tyr21_Arg22delinsTer
  • NC_000018.10:g.60372286_60372287delTG
  • NC_000018.9:g.58039520_58039521del
  • NM_005912.2:c.63_64delCA
  • p.Tyr21Terfs
  • NM_005912.2(MC4R):c.63_64delCA
Links:
dbSNP: rs770293321
NCBI 1000 Genomes Browser:
rs770293321
Molecular consequence:
  • NM_005912.3:c.63_64del - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Obesity (EO Obesity)
Synonyms:
OBESITY, SUSCEPTIBILITY TO; Obesity disorder
Identifiers:
MONDO: MONDO:0011122; MeSH: D009765; MedGen: C0028754; Orphanet: 71529; OMIM: 601665; Human Phenotype Ontology: HP:0001513

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000692293Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospitalno assertion criteria providedPathogenic
(Sep 8, 2016)
germlineclinical testing

SCV001422869Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedUncertain significance
(Jan 22, 2020)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital, SCV000692293.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Broad Institute Rare Disease Group, Broad Institute, SCV001422869.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The p.Tyr21Terfs variant in MC4R has not been previously reported in individuals with obesity and has been identified in 0.007% (2/30616) of South Asian chromosomes and 0.006% (1/16150) African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs770293321). This variant has also been reported in ClinVar (Variation ID: 492860). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 21 and leads to a premature termination codon at the same position. This alteration is then predicted to lead to a truncated protein since this is a single exon gene that is not predicted to undergo nonsense mediated decay. Heterozygous loss of function of the MC4R gene is an established disease mechanism in obesity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate, PM2_supporting (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 6, 2021

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