NM_002461.3(MVD):c.746T>C (p.Phe249Ser) AND Porokeratosis 7, multiple types

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 9, 2024
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:: RCV000239486.2

Allele description [Variation Report for NM_002461.3(MVD):c.746T>C (p.Phe249Ser)]

NM_002461.3(MVD):c.746T>C (p.Phe249Ser)

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.746T>C (p.Phe249Ser)

HGVS:

NC_000016.10:g.88655350A>G
NG_007291.1:g.700T>C
NG_052674.1:g.12804T>C
NM_002461.2:c.746T>C
NM_002461.3:c.746T>CMANE SELECT
NP_002452.1:p.Phe249Ser
LRG_52:g.700T>C
NC_000016.9:g.88721758A>G
NM_002461.1:c.746T>C
P53602:p.Phe249Ser

Protein change:

F249S; PHE249SER

Links:

UniProtKB: P53602#VAR_075058; OMIM: 603236.0001; dbSNP: rs761991070

NCBI 1000 Genomes Browser:

rs761991070

Molecular consequence:

NM_002461.3:c.746T>C - 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
SCV000297828	OMIM	no assertion criteria provided	Pathogenic (Jul 23, 2015)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 21161278, 26202976
SCV005398969	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 9, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26202976, 27422687, 29722423, 38283795, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000297828

OMIM

no assertion criteria provided

Pathogenic
(Jul 23, 2015)

germline

literature only

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

SCV005398969

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 9, 2024)

germline

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

A novel locus for disseminated superficial actinic porokeratosis maps to chromosome 16q24.1-24.3.

Luan J, Niu Z, Zhang J, Crosby ME, Zhang Z, Chu X, Wang Z, Huang W, Xiang L, Zheng Z.

Hum Genet. 2011 Mar;129(3):329-34. doi: 10.1007/s00439-010-0929-x. Epub 2010 Dec 14.

PubMed [citation]

PMID:: 21161278

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

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000297828.1

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

Description

In 12 affected members of a 4-generation Chinese family with disseminated superficial actinic porokeratosis-7 (POROK7; 614714), originally reported by Luan et al. (2011), Zhang et al. (2015) identified heterozygosity for a c.746T-C transition (c.746T-C, NM_002461.1) in exon 7 of the MVD gene, resulting in a phe249-to-ser (F249S) substitution. The mutation segregated fully with disease in the family. Subsequent analysis of 134 Chinese probands with porokeratosis revealed that either the F249S mutation or an N292S mutation (603236.0002) was present in heterozygosity in 50 of the patients, thus accounting for 81% of all porokeratosis patients with MVD mutations. In 1 female proband, Zhang et al. (2015) detected heterozygosity for F249S in the MVD gene as well as heterozygosity for a D79N substitution in the MVK gene (251170), but noted that the patient did not exhibit a more severe phenotype or earlier age of onset or any other unique clinical features.

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005398969.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is likely a mechanism of disease in this gene and is associated with porokeratosis 7, multiple types (MIM#614714). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Variable penetrance has been described as it is suspected to cause disease only when a somatic second hit occurs (PMID: 38283795) . (I) 0115 - Variants in this gene are known to have variable expressivity. Individuals in the same family carrying the same pathogenic variant showed different clinical manifestations and severity (PMID: 26202976). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated mevalonate 5-diphosphate decarboxylase C-terminal domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in many individuals with porokeratosis, including both familial cases and sporadic cases (PMIDs: 26202976, 27422687, 29722423, 38283795). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in a large family (PMID: 26202976). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 30, 2024

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