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NM_182914.3(SYNE2):c.13570G>A (p.Glu4524Lys) AND Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 29, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000548718.13

Allele description [Variation Report for NM_182914.3(SYNE2):c.13570G>A (p.Glu4524Lys)]

NM_182914.3(SYNE2):c.13570G>A (p.Glu4524Lys)

Gene:
SYNE2:spectrin repeat containing nuclear envelope protein 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q23.2
Genomic location:
Preferred name:
NM_182914.3(SYNE2):c.13570G>A (p.Glu4524Lys)
HGVS:
  • NC_000014.9:g.64126342G>A
  • NG_011756.2:g.369444G>A
  • NM_015180.6:c.13570G>A
  • NM_182914.3:c.13570G>AMANE SELECT
  • NP_055995.4:p.Glu4524Lys
  • NP_878918.2:p.Glu4524Lys
  • NP_878918.2:p.Glu4524Lys
  • LRG_872t1:c.13570G>A
  • LRG_872:g.369444G>A
  • LRG_872p1:p.Glu4524Lys
  • NC_000014.8:g.64593060G>A
  • NG_011756.1:g.278378G>A
  • NM_182914.2:c.13570G>A
Protein change:
E4524K
Links:
dbSNP: rs143646847
NCBI 1000 Genomes Browser:
rs143646847
Molecular consequence:
  • NM_015180.6:c.13570G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_182914.3:c.13570G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Emery-Dreifuss muscular dystrophy 5, autosomal dominant (EDMD5)
Synonyms:
EMERY-DREIFUSS MUSCULAR DYSTROPHY 5
Identifiers:
MONDO: MONDO:0013072; MedGen: C2751805; Orphanet: 261; OMIM: 612999

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000387503Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)		Benign
(Jan 12, 2018) 		germlineclinical testing

Citation Link,

SCV000648840Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 29, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000387503.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000648840.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 4524 of the SYNE2 protein (p.Glu4524Lys). This variant is present in population databases (rs143646847, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 313589). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 15, 2024