VCV000056904.4 - ClinVar

NM_005664.4(MKRN3):c.482dup (p.Ala162fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005664.4(MKRN3):c.482dup (p.Ala162fs)

Variation ID: 56904 Accession: VCV000056904.4

Type and length

Duplication, 1 bp

Location

Cytogenetic: 15q11.2 15: 23566257-23566258 (GRCh38) [ NCBI UCSC ] 15: 23811404-23811405 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 10, 2017	Nov 20, 2023	Mar 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005664.4:c.482dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005655.1:p.Ala162fs	frameshift
NM_005664.3:c.482dupC
NC_000015.10:g.23566264dup
NC_000015.9:g.23811411dup
NG_012875.3:g.5958dup
LRG_1045:g.5958dup
LRG_1045t1:c.482dup	LRG_1045p1:p.Ala162fs

... more HGVS ... less HGVS

Protein change

A162fs

Other names

Canonical SPDI

NC_000015.10:23566257:CCCCCCC:CCCCCCCC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA7429380 OMIM: 603856.0004 dbSNP: rs763195944 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MKRN3		No evidence available	No evidence available	GRCh38 GRCh38 GRCh37	71	375

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Precocious puberty, central, 2	Pathogenic (1)	no assertion criteria provided	Jun 27, 2013	RCV000050241.3
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 5, 2022	RCV001787846.2
MKRN3-related disorder	Pathogenic (1)	criteria provided, single submitter	Mar 24, 2023	RCV003415821.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 05, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002030919.2 First in ClinVar: Dec 12, 2021 Last updated: Dec 03, 2022	Comment: Frameshift variant predicted to result in protein truncation, as the last 346 amino acids are replaced with 14 different amino acids, and other loss-of-function variants … (more) Frameshift variant predicted to result in protein truncation, as the last 346 amino acids are replaced with 14 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Also known as c.475_476insC and c.482_483insC; This variant is associated with the following publications: (PMID: 30675365, 24628548, 26431553, 31589614, 33383582, 32676665, 23738509, 25011910) (less)
Pathogenic (Mar 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MKRN3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004113133.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The MKRN3 c.482dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala162Glyfs15). This variant has been reported to be causative for … (more) The MKRN3 c.482dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala162Glyfs15). This variant has been reported to be causative for central precocious puberty (Abreu et al. 2013. PubMed ID: 23738509; Macedo et al. 2014. PubMed ID: 24628548; Schreiner et al. 2014. PubMed ID: 25011910; Simon et al. 2016. PubMed ID: 26431553; Bessa et al. 2017. PubMed ID: 27225315). Please note that MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region and all affected individuals inherited the pathogenic variants from their fathers. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-23811404-G-GC). Frameshift variants in MKRN3 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Jun 27, 2013)	no assertion criteria provided Method: literature only	PRECOCIOUS PUBERTY, CENTRAL, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000082833.2 First in ClinVar: Aug 01, 2013 Last updated: Sep 10, 2017	Publications: PubMed (2) PubMed: 23738509‚ 26431553 Comment on evidence: In 2 Brazilian brothers and a brother and sister from a family of European ancestry with central precocious puberty (CPPB2; 615346), Abreu et al. (2013) … (more) In 2 Brazilian brothers and a brother and sister from a family of European ancestry with central precocious puberty (CPPB2; 615346), Abreu et al. (2013) identified heterozygosity for a 1-bp insertion (c.475_476insC) in the MKRN3 gene, causing a frameshift predicted to result in a premature termination codon (Ala162GlyfsTer14) and a truncated protein of 176 amino acids. Consistent with the pattern of a paternally expressed imprinted gene, in both families the mutation was inherited from an unaffected father, who likely inherited it from his mother. Abreu et al. (2013) stated that it was possible that the 2 families were distantly related. In 17 affected girls from 8 families with central precocious puberty, Simon et al. (2016) identified heterozygosity for the previously reported 1-bp insertion in the MKRN3 gene, which these authors designated as c.482insC, resulting in a premature termination codon (Ala162GlyfsTer15). The mutation segregated with disease in the families and was found in each of 6 unaffected carrier fathers tested. Noting the high frequency of this mutation, Simon et al. (2016) concluded that the cytosine homopolymer between nucleotides 476 and 482 is a mutation hotspot. (less)

Comment:

Frameshift variant predicted to result in protein truncation, as the last 346 amino acids are replaced with 14 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Also known as c.475_476insC and c.482_483insC; This variant is associated with the following publications: (PMID: 30675365, 24628548, 26431553, 31589614, 33383582, 32676665, 23738509, 25011910)

Comment:

The MKRN3 c.482dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala162Glyfs*15). This variant has been reported to be causative for central precocious puberty (Abreu et al. 2013. PubMed ID: 23738509; Macedo et al. 2014. PubMed ID: 24628548; Schreiner et al. 2014. PubMed ID: 25011910; Simon et al. 2016. PubMed ID: 26431553; Bessa et al. 2017. PubMed ID: 27225315). Please note that MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region and all affected individuals inherited the pathogenic variants from their fathers. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-23811404-G-GC). Frameshift variants in MKRN3 are expected to be pathogenic. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.	Simon D	European journal of endocrinology	2016	PMID: 26431553
Central precocious puberty caused by mutations in the imprinted gene MKRN3.	Abreu AP	The New England journal of medicine	2013	PMID: 23738509

Text-mined citations for rs763195944 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 19, 2024

ClinVar Genomic variation as it relates to human health

NM_005664.4(MKRN3):c.482dup (p.Ala162fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs763195944 ...