NM_001164508.2(NEB):c.3255+1G>T AND Nemaline myopathy 2

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 13, 2023
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:: RCV000667228.10

Allele description [Variation Report for NM_001164508.2(NEB):c.3255+1G>T]

NM_001164508.2(NEB):c.3255+1G>T

Gene:

NEB:nebulin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q23.3

Genomic location:

Preferred name:

NM_001164508.2(NEB):c.3255+1G>T

HGVS:

NC_000002.12:g.151679720C>A
NG_009382.2:g.59768G>T
NM_001164507.2:c.3255+1G>T
NM_001164508.2:c.3255+1G>TMANE SELECT
NM_001271208.2:c.3255+1G>T
NM_004543.5:c.3255+1G>T
LRG_202t1:c.3255+1G>T
LRG_202:g.59768G>T
NC_000002.11:g.152536234C>A
NM_001271208.1:c.3255+1G>T

Links:

dbSNP: rs375628303

NCBI 1000 Genomes Browser:

rs375628303

Molecular consequence:

NM_001164507.2:c.3255+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001164508.2:c.3255+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001271208.2:c.3255+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_004543.5:c.3255+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Nemaline myopathy 2 (NEM2)
Synonyms:: Nemaline myopathy caused by mutation in the nebulin gene; Nemaline myopathy 2, autosomal recessive
Identifiers:: MONDO: MONDO:0009725; MedGen: C1850569; OMIM: 256030

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000791648	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (May 19, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16917880, 25205138 Citation Link,
SCV000893563	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000956305	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16917880, 28492532
SCV002077745	Natera, Inc.	no assertion criteria provided	Pathogenic (Jan 19, 2021)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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

Mutation update: the spectra of nebulin variants and associated myopathies.

Lehtokari VL, Kiiski K, Sandaradura SA, Laporte J, Repo P, Frey JA, Donner K, Marttila M, Saunders C, Barth PG, den Dunnen JT, Beggs AH, Clarke NF, North KN, Laing NG, Romero NB, Winder TL, Pelin K, Wallgren-Pettersson C.

Hum Mutat. 2014 Dec;35(12):1418-26. doi: 10.1002/humu.22693.

PubMed [citation]

PMID:: 25205138
PMCID:: PMC4295925

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

See all PubMed Citations (4)

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 Counsyl, SCV000791648.1

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

#	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 Fulgent Genetics, Fulgent Genetics, SCV000893563.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000956305.4

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

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 32, but is expected to preserve the integrity of the reading-frame (PMID: 16917880). ClinVar contains an entry for this variant (Variation ID: 552035). This variant is also known as g.53437G>T. Disruption of this splice site has been observed in individuals with nemaline myopathy (PMID: 16917880). This variant is present in population databases (rs375628303, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 32 of the NEB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product.

#	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 Natera, Inc., SCV002077745.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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