NM_005797.4(MPZL2):c.72del (p.Ile24fs) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 18, 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:: RCV000820138.13

Allele description

NM_005797.4(MPZL2):c.72del (p.Ile24fs)

Gene:

MPZL2:myelin protein zero like 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_005797.4(MPZL2):c.72del (p.Ile24fs)

HGVS:

NC_000011.10:g.118263084del
NM_005797.4:c.72delMANE SELECT
NM_144765.3:c.72del
NP_005788.1:p.Ile24fs
NP_658911.1:p.Ile24fs
NC_000011.9:g.118133799del
NM_005797.3:c.72delA

Protein change:

I24fs

Links:

OMIM: 604873.0001; dbSNP: rs752672077

NCBI 1000 Genomes Browser:

rs752672077

Molecular consequence:

NM_005797.4:c.72del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_144765.3:c.72del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000960835	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29961571, 29982980, 28492532
SCV001825233	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 8, 2023)	germline	clinical testing	Citation Link,
SCV001953019	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001967065	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

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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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

MPZL2, Encoding the Epithelial Junctional Protein Myelin Protein Zero-like 2, Is Essential for Hearing in Man and Mouse.

Wesdorp M, Murillo-Cuesta S, Peters T, Celaya AM, Oonk A, Schraders M, Oostrik J, Gomez-Rosas E, Beynon AJ, Hartel BP, Okkersen K, Koenen HJPM, Weeda J, Lelieveld S, Voermans NC, Joosten I, Hoyng CB, Lichtner P, Kunst HPM, Feenstra I, de Bruijn SE; DOOFNL Consortium, et al.

Am J Hum Genet. 2018 Jul 5;103(1):74-88. doi: 10.1016/j.ajhg.2018.05.011. Epub 2018 Jun 28.

PubMed [citation]

PMID:: 29961571
PMCID:: PMC6037131

MPZL2 is a novel gene associated with autosomal recessive nonsyndromic moderate hearing loss.

Bademci G, Abad C, Incesulu A, Rad A, Alper O, Kolb SM, Cengiz FB, Diaz-Horta O, Silan F, Mihci E, Ocak E, Najafi M, Maroofian R, Yilmaz E, Nur BG, Duman D, Guo S, Sant DW, Wang G, Monje PV, Haaf T, Blanton SH, et al.

Hum Genet. 2018 Jul;137(6-7):479-486. doi: 10.1007/s00439-018-1901-4. Epub 2018 Jul 7.

PubMed [citation]

PMID:: 29982980
PMCID:: PMC6478175

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000960835.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Ile24Metfs*22) in the MPZL2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MPZL2 cause disease. This variant is present in population databases (rs752672077, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with nonsyndromic hearing loss (PMID: 29961571, 29982980). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585268). 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 GeneDx, SCV001825233.6

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29961571, 29982980, 34426522, 34062854, 33234333, 33594163, 27535533, 35599849, 36147510)

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001953019.1

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001967065.1

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

Last Updated: Aug 4, 2024

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