NM_000431.4(MVK):c.1129G>A (p.Val377Ile) AND multiple conditions

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000627780.13

Allele description [Variation Report for NM_000431.4(MVK):c.1129G>A (p.Val377Ile)]

NM_000431.4(MVK):c.1129G>A (p.Val377Ile)

Gene:

MVK:mevalonate kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.11

Genomic location:

Preferred name:

NM_000431.4(MVK):c.1129G>A (p.Val377Ile)

HGVS:

NC_000012.12:g.109596515G>A
NG_007702.1:g.27821G>A
NM_000431.4:c.1129G>AMANE SELECT
NM_001114185.3:c.1129G>A
NM_001301182.2:c.973G>A
NP_000422.1:p.Val377Ile
NP_001107657.1:p.Val377Ile
NP_001288111.1:p.Val325Ile
LRG_156t1:c.1129G>A
LRG_156:g.27821G>A
NC_000012.11:g.110034320G>A
NM_000431.2:c.1129G>A
NM_000431.3:c.1129G>A
NM_000431.4:c.1129G>A
NM_001114185.2:c.1129G>A
NM_001301182.1:c.973G>A
Q03426:p.Val377Ile

Protein change:

V325I; VAL377ILE

Links:

UniProtKB: Q03426#VAR_004027; OMIM: 251170.0002; dbSNP: rs28934897

NCBI 1000 Genomes Browser:

rs28934897

Molecular consequence:

NM_000431.4:c.1129G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001114185.3:c.1129G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001301182.2:c.973G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mevalonic aciduria (MEVA)
Identifiers:: MONDO: MONDO:0012481; MedGen: C1959626; Orphanet: 29; OMIM: 610377

Name:: Porokeratosis 3, disseminated superficial actinic type (DSAP1)
Synonyms:: Porokeratosis, disseminated superficial actinic 1; POROKERATOSIS 3, MULTIPLE TYPES; POROKERATOSIS 3, MIBELLI TYPE
Identifiers:: MONDO: MONDO:0008293; MedGen: C1867981; OMIM: 175900

Name:: Hyperimmunoglobulin D with periodic fever (HIDS)
Synonyms:: Hyperimmunoglobulinemia D and periodic fever syndrome; Periodic fever Dutch type; Hyperimmunoglobulinemia D; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009849; MedGen: C0398691; Orphanet: 343; OMIM: 260920

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000634151	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11313769, 12634869, 15536479, 10369261, 26977311, 28492532
SCV000893959	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003931223	GenomeConnect - Brain Gene Registry	no classification provided	not provided	maternal	phenotyping only

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000634151

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000893959

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 31, 2018)

unknown

clinical testing

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

SCV003931223

GenomeConnect - Brain Gene Registry

no classification provided

not provided

maternal

phenotyping only

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	maternal	unknown	1	not provided	not provided	1	not provided	phenotyping only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome.

Cuisset L, Drenth JP, Simon A, Vincent MF, van der Velde Visser S, van der Meer JW, Grateau G, Delpech M; International Hyper-IgD Study Group..

Eur J Hum Genet. 2001 Apr;9(4):260-6.

PubMed [citation]

PMID:: 11313769

Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands.

Houten SM, van Woerden CS, Wijburg FA, Wanders RJ, Waterham HR.

Eur J Hum Genet. 2003 Feb;11(2):196-200.

PubMed [citation]

PMID:: 12634869

See all PubMed Citations (7)

PMC

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.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Invitae, SCV000634151.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 377 of the MVK protein (p.Val377Ile). This variant is present in population databases (rs28934897, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hyper IgD syndrome (HIDS), and is one of the most commonly reported variants found in HIDS patients (PMID: 10369261, 11313769, 12634869, 15536479, 26977311). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11929). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects MVK function (PMID: 10369261, 26977311). 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893959.1

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

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

From GenomeConnect - Brain Gene Registry, SCV003931223.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	phenotyping only	not provided

Description

Variant classified as Pathogenic and reported on 12-06-2016 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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

Last Updated: May 19, 2024

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