NM_031448.6(C19orf12):c.171_181del (p.Gly58fs) AND Hereditary spastic paraplegia 43

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 24, 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:: RCV001044832.8

Allele description [Variation Report for NM_031448.6(C19orf12):c.171_181del (p.Gly58fs)]

NM_031448.6(C19orf12):c.171_181del (p.Gly58fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

19q12

Genomic location:

Preferred name:

NM_031448.6(C19orf12):c.171_181del (p.Gly58fs)

Other names:

C19ORF12, 11-BP DEL, NT204

HGVS:

NC_000019.10:g.29702967_29702977del
NG_031970.2:g.17823_17833del
NM_001031726.4:c.171_181del
NM_001256046.3:c.171_181del
NM_001256047.2:c.171_181del
NM_001282929.1:c.-22_-12del
NM_001282930.3:c.-22_-12del
NM_001282931.3:c.-22_-12del
NM_031448.6:c.171_181delMANE SELECT
NP_001026896.2:p.Gly69fs
NP_001026896.3:p.Gly58fs
NP_001242975.1:p.Gly58fs
NP_001242976.1:p.Gly58fs
NP_113636.2:p.Gly58fs
NC_000019.10:g.29702957_29702967del
NC_000019.9:g.30193864_30193874del
NC_000019.9:g.30193874_30193884del
NM_001031726.2:c.204_214del
NM_001031726.3:c.204_214del
NM_001031726.3:c.204_214del11
NM_001031726.4:c.171_181del11
NP_001026896.2:p.Gly69ArgfsTer10

Protein change:

G58fs

Links:

OMIM: 614297.0001; dbSNP: rs515726204

NCBI 1000 Genomes Browser:

rs515726204

Molecular consequence:

NM_001282929.1:c.-22_-12del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001282930.3:c.-22_-12del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001282931.3:c.-22_-12del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001031726.4:c.171_181del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001256046.3:c.171_181del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001256047.2:c.171_181del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_031448.6:c.171_181del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Hereditary spastic paraplegia 43
Synonyms:: Spastic paraplegia 43, autosomal recessive
Identifiers:: MONDO: MONDO:0014024; MedGen: C2680446; Orphanet: 320370; OMIM: 615043

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001208652	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21981780, 23436634, 28641177, 30392167, 28492532
SCV002059010	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:21981780

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001208652

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002059010

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 3, 2022)

germline

clinical testing

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

PMID:21981780

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	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

Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation.

Schulte EC, Claussen MC, Jochim A, Haack T, Hartig M, Hempel M, Prokisch H, Haun-Jünger U, Winkelmann J, Hemmer B, Förschler A, Ilg R.

Mov Disord. 2013 Feb;28(2):224-7. doi: 10.1002/mds.25256. Epub 2012 Nov 19.

PubMed [citation]

PMID:: 23436634

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001208652.5

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

Description

This sequence change creates a premature translational stop signal (p.Gly69Argfs*10) in the C19orf12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 84 amino acid(s) of the C19orf12 protein. This variant is present in population databases (rs515726204, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive neurodegeneration with brain iron accumulation or mitochondria protein-associated neurodegeneration (PMID: 21981780, 23436634, 28641177, 30392167). It is commonly reported in individuals of Polish ancestry (PMID: 21981780, 23436634, 28641177, 30392167). ClinVar contains an entry for this variant (Variation ID: 31155). 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 3billion, SCV002059010.1

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

Description

Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported to be associated with C19orf12 related disorder (ClinVar ID: VCV000031155, PMID:21981780).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000100, PM2_M). 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: Oct 20, 2024

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