NM_001164508.2(NEB):c.24299C>T (p.Ser8100Leu) AND Nemaline myopathy 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 6, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000531322.5

Allele description [Variation Report for NM_001164508.2(NEB):c.24299C>T (p.Ser8100Leu)]

NM_001164508.2(NEB):c.24299C>T (p.Ser8100Leu)

Genes:

NEB:nebulin [Gene - OMIM - HGNC]
RIF1:replication timing regulatory factor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q23.3

Genomic location:

Preferred name:

NM_001164508.2(NEB):c.24299C>T (p.Ser8100Leu)

HGVS:

NC_000002.12:g.151497627G>A
NG_009382.2:g.241861C>T
NM_001164507.2:c.24299C>T
NM_001164508.2:c.24299C>TMANE SELECT
NM_001271208.2:c.24404C>T
NM_004543.5:c.18826-1259C>T
NP_001157979.2:p.Ser8100Leu
NP_001157980.2:p.Ser8100Leu
NP_001258137.2:p.Ser8135Leu
LRG_202t1:c.24404C>T
LRG_202:g.241861C>T
NC_000002.11:g.152354141G>A
NM_001271208.1:c.24404C>T

Protein change:

S8100L

Links:

dbSNP: rs759261311

NCBI 1000 Genomes Browser:

rs759261311

Molecular consequence:

NM_004543.5:c.18826-1259C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001164507.2:c.24299C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164508.2:c.24299C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001271208.2:c.24404C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000640741	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 6, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002083973	Natera, Inc.	no assertion criteria provided	Uncertain significance (Feb 9, 2021)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000640741

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 6, 2022)

germline

clinical testing

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

SCV002083973

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Feb 9, 2021)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV000640741.3

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

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 8135 of the NEB protein (p.Ser8135Leu). This variant is present in population databases (rs759261311, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 465580). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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., SCV002083973.1

#	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: Feb 7, 2023

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