NM_031448.6(C19orf12):c.391A>G (p.Lys131Glu) AND Neurodegeneration with brain iron accumulation 4

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Dec 3, 2021
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:: RCV000024154.12

Allele description [Variation Report for NM_031448.6(C19orf12):c.391A>G (p.Lys131Glu)]

NM_031448.6(C19orf12):c.391A>G (p.Lys131Glu)

Gene:

C19orf12:chromosome 19 open reading frame 12 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q12

Genomic location:

Preferred name:

NM_031448.6(C19orf12):c.391A>G (p.Lys131Glu)

Other names:

C19ORF12, LYS142GLU

HGVS:

NC_000019.10:g.29702747T>C
NG_031970.2:g.18043A>G
NM_001031726.4:c.391A>G
NM_001256046.3:c.*12A>G
NM_001256047.2:c.391A>G
NM_001282929.1:c.199A>G
NM_001282930.3:c.199A>G
NM_001282931.3:c.199A>G
NM_031448.6:c.391A>GMANE SELECT
NP_001026896.2:p.Lys142Glu
NP_001026896.3:p.Lys131Glu
NP_001242976.1:p.Lys131Glu
NP_001269858.1:p.Lys67Glu
NP_001269859.1:p.Lys67Glu
NP_001269860.1:p.Lys67Glu
NP_113636.2:p.Lys131Glu
NC_000019.9:g.30193654T>C
NM_001031726.2:c.424A>G
NM_001031726.3:c.424A>G
NM_031448.6:c.391A>G

Protein change:

K131E; LYS142GLU

Links:

OMIM: 614297.0004; dbSNP: rs146170087

NCBI 1000 Genomes Browser:

rs146170087

Molecular consequence:

NM_001256046.3:c.*12A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001031726.4:c.391A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001256047.2:c.391A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001282929.1:c.199A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001282930.3:c.199A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001282931.3:c.199A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_031448.6:c.391A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Neurodegeneration with brain iron accumulation 4 (NBIA4)
Synonyms:: MITOCHONDRIAL PROTEIN-ASSOCIATED NEURODEGENERATION
Identifiers:: MONDO: MONDO:0013674; MedGen: C3280371; Orphanet: 289560; OMIM: 614298

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000845637	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 7, 2018)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001141042	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Dec 3, 2021)	unknown	clinical testing	Citation Link,
SCV005091446	Solve-RD Consortium	no assertion criteria provided	Likely pathogenic (Jun 1, 2022)	inherited	provider interpretation

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000845637

Genomic Research Center, Shahid Beheshti University of Medical Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 7, 2018)

inherited

clinical testing

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

SCV001141042

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(Dec 3, 2021)

unknown

clinical testing

Citation Link,

SCV005091446

Solve-RD Consortium

no assertion criteria provided

Likely pathogenic
(Jun 1, 2022)

inherited

provider interpretation

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	inherited	yes	not provided	not provided	not provided	not provided	not provided	provider interpretation
not provided	inherited	no	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.

Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, Roeber S, Tarabin V, Dusi S, Krajewska-Walasek M, Jozwiak S, Hempel M, Winkelmann J, Elstner M, Oexle K, Klopstock T, Mueller-Felber W, Gasser T, Trenkwalder C, Tiranti V, Kretzschmar H, Schmitz G, et al.

Am J Hum Genet. 2011 Oct 7;89(4):543-50. doi: 10.1016/j.ajhg.2011.09.007.

PubMed [citation]

PMID:: 21981780
PMCID:: PMC3188837

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, SCV000045445.3

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

Description

In a Polish patient with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified compound heterozygosity for 2 mutations in the C19ORF12 gene: a c.424A-G transition (c.424A-G, NM_001031726.2), resulting in a lys142-to-glu (K142E) substitution and G69R (614297.0003). Neither mutation was found in 750 control chromosomes. This patient had a relatively mild form of the disorder, with only impairment of fine motor skills beginning at age 14 years. MRI performed at age 12 for a pituitary adenoma showed brain iron accumulation as an incidental finding. This same genotype (G69R and K142E) was found in 1 of 676 patients with parkinsonism. This patient presented with paranoid hallucinations at age 25 years. By age 49, he was diagnosed with Parkinson disease, with rigidity, akinesia, and mild tremor. He also had axial signs, dystonia of the legs with muscle cramps, hypophonia, hypomimia, vivid dreams, sleep disturbance, optic hallucinations, and cognitive decline. CT scan showed marked cerebral atrophy, but MRI was not performed. Both of these patients had a milder form of the disorder compared to patients with other C19ORF12 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 Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000845637.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	inherited	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Mendelics, SCV001141042.2

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

#	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 Solve-RD Consortium, SCV005091446.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

Description

Variant confirmed as disease-causing by referring clinical team

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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000045445	OMIM	flagged submission Reason: Older claim that does not account for recent evidence Notes: None	Pathogenic (Oct 7, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000045445

OMIM

flagged submission

Reason: Older claim that does not account for recent evidence

Notes: None

Pathogenic
(Oct 7, 2011)

germline

literature only

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

Last Updated: Dec 22, 2024

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