NM_031448.6(C19orf12):c.215C>T (p.Pro72Leu) AND Neurodegeneration with brain iron accumulation 4

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Sep 1, 2022
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:: RCV000211114.5

Allele description [Variation Report for NM_031448.6(C19orf12):c.215C>T (p.Pro72Leu)]

NM_031448.6(C19orf12):c.215C>T (p.Pro72Leu)

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.215C>T (p.Pro72Leu)

Other names:

C19ORF12, PRO83LEU (rs201987973); P83L

HGVS:

NC_000019.10:g.29702923G>A
NG_031970.2:g.17867C>T
NM_001031726.4:c.215C>T
NM_001256046.3:c.215C>T
NM_001256047.2:c.215C>T
NM_001282929.1:c.23C>T
NM_001282930.3:c.23C>T
NM_001282931.3:c.23C>T
NM_031448.6:c.215C>TMANE SELECT
NP_001026896.3:p.Pro72Leu
NP_001242975.1:p.Pro72Leu
NP_001242976.1:p.Pro72Leu
NP_001269858.1:p.Pro8Leu
NP_001269859.1:p.Pro8Leu
NP_001269860.1:p.Pro8Leu
NP_113636.2:p.Pro72Leu
NC_000019.9:g.30193830G>A

Protein change:

P72L; PRO83LEU

Links:

OMIM: 614297.0008; dbSNP: rs201987973

NCBI 1000 Genomes Browser:

rs201987973

Molecular consequence:

NM_001031726.4:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001256046.3:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001256047.2:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282929.1:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282930.3:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282931.3:c.23C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_031448.6:c.215C>T - 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
SCV000268062	OMIM	no assertion criteria provided	Pathogenic (Jan 15, 2013)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 26187298, 23269600
SCV002562212	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002572595	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26187298, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000268062

OMIM

no assertion criteria provided

Pathogenic
(Jan 15, 2013)

germline

literature only

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

SCV002562212

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

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

SCV002572595

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 1, 2022)

germline

clinical testing

PubMed (2)
[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	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN.

Hogarth P, Gregory A, Kruer MC, Sanford L, Wagoner W, Natowicz MR, Egel RT, Subramony SH, Goldman JG, Berry-Kravis E, Foulds NC, Hammans SR, Desguerre I, Rodriguez D, Wilson C, Diedrich A, Green S, Tran H, Reese L, Woltjer RL, Hayflick SJ.

Neurology. 2013 Jan 15;80(3):268-75. doi: 10.1212/WNL.0b013e31827e07be. Epub 2012 Dec 26.

PubMed [citation]

PMID:: 23269600
PMCID:: PMC3589182

Behr syndrome with homozygous C19ORF12 mutation.

Kleffner I, Wessling C, Gess B, Korsukewitz C, Allkemper T, Schirmacher A, Young P, Senderek J, Husstedt IW.

J Neurol Sci. 2015 Oct 15;357(1-2):115-8. doi: 10.1016/j.jns.2015.07.009. Epub 2015 Jul 9.

PubMed [citation]

PMID:: 26187298

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000268062.3

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

Description

In 2 sisters, born of consanguineous Turkish parents, with neurodegeneration with brain iron accumulation-4 (NBIA4; 614298), Kleffner et al. (2015) identified a homozygous c.248C-T transition (rs201987973) in the C19ORF12 gene, resulting in a pro83-to-leu (P83L) substitution at a highly conserved residue. The mutation segregated with the disorder in the family and was not found in the Exome Variant Server or 1000 Genomes Project databases, or in 96 control individuals. Functional studies of the variant and studies of patient cells were not performed, but Kleffner et al. (2015) noted that the same variant had previously been identified in 2 other families with the disorder by Hogarth et al. (2013). The phenotype in the sisters included progressive optic atrophy, spastic tetraparesis, cerebellar signs, and cognitive decline, reminiscent of Behr syndrome (210000).

#	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 Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV002562212.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002572595.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.74). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 26187298). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 26187298). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Feb 25, 2023

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