NM_002461.3(MVD):c.875A>G (p.Asn292Ser) AND Porokeratosis 7, multiple types

Germline classification:: Pathogenic (2 submissions)
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:: RCV000239520.3

Allele description [Variation Report for NM_002461.3(MVD):c.875A>G (p.Asn292Ser)]

NM_002461.3(MVD):c.875A>G (p.Asn292Ser)

Gene:

MVD:mevalonate diphosphate decarboxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q24.2

Genomic location:

Preferred name:

NM_002461.3(MVD):c.875A>G (p.Asn292Ser)

HGVS:

NC_000016.10:g.88655221T>C
NG_007291.1:g.829A>G
NG_052674.1:g.12933A>G
NM_002461.3:c.875A>GMANE SELECT
NP_002452.1:p.Asn292Ser
LRG_52:g.829A>G
NC_000016.9:g.88721629T>C
NM_002461.1:c.875A>G
P53602:p.Asn292Ser

Protein change:

N292S; ASN292SER

Links:

UniProtKB: P53602#VAR_075059; OMIM: 603236.0002; dbSNP: rs755948940

NCBI 1000 Genomes Browser:

rs755948940

Molecular consequence:

NM_002461.3:c.875A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Porokeratosis 7, multiple types
Synonyms:: POROK7
Identifiers:: MONDO: MONDO:0013868; MedGen: C3553549; OMIM: 614714

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000297829	OMIM	no assertion criteria provided	Pathogenic (Jul 23, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004047069	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000297829

OMIM

no assertion criteria provided

Pathogenic
(Jul 23, 2015)

germline

literature only

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

SCV004047069

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genomic variations of the mevalonate pathway in porokeratosis.

Zhang Z, Li C, Wu F, Ma R, Luan J, Yang F, Liu W, Wang L, Zhang S, Liu Y, Gu J, Hua W, Fan M, Peng H, Meng X, Song N, Bi X, Gu C, Zhang Z, Huang Q, Chen L, Xiang L, et al.

Elife. 2015 Jul 23;4:e06322. doi: 10.7554/eLife.06322. Erratum in: Elife. 2016 Jan 27;5:e14383. doi: 10.7554/eLife.14383.

PubMed [citation]

PMID:: 26202976
PMCID:: PMC4511816

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, SCV000297829.1

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

Description

In 3 brothers and their affected mother from a Chinese family with porokeratosis (POROK7; 614714), Zhang et al. (2015) identified heterozygosity for a c.875A-G transition (c.875A-G, NM_002461.1) in exon 7 of the MVD gene, resulting in an asn292-to-ser (N292S) substitution. The mutation segregated with disease in the family and was not found in 270 ethnically matched controls. The male proband exhibited discrete red-brown annular keratotic papules and maculopapules on his chest. The authors noted that either the N292S or the F249S mutation (603236.0001) was present in heterozygosity in 50 porokeratosis probands, thus accounting for 81% of all porokeratosis patients with MVD mutations.

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV004047069.1

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

Description

The amino acid Asn at position 292 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Asn292Ser in MVD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Asn292Ser variant is reported in gnomAD with the allele frequency of 0.00000928 and is novel (not in any individuals) in 1000 Genomes. It is a hotspot mutation and along with c.746T>C variant accounts for 81% cases (Zhang Z et al, Qian W et al). 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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