NM_182961.4(SYNE1):c.9715C>G (p.Gln3239Glu) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Feb 16, 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:: RCV000370965.19

Allele description [Variation Report for NM_182961.4(SYNE1):c.9715C>G (p.Gln3239Glu)]

NM_182961.4(SYNE1):c.9715C>G (p.Gln3239Glu)

Gene:

SYNE1:spectrin repeat containing nuclear envelope protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q25.2

Genomic location:

Preferred name:

NM_182961.4(SYNE1):c.9715C>G (p.Gln3239Glu)

HGVS:

NC_000006.12:g.152369064G>C
NG_012855.2:g.273336C>G
NM_033071.5:c.9736C>G
NM_182961.4:c.9715C>GMANE SELECT
NP_149062.1:p.Gln3246Glu
NP_149062.2:p.Gln3246Glu
NP_892006.3:p.Gln3239Glu
LRG_427t1:c.9715C>G
LRG_427t2:c.9736C>G
LRG_427:g.273336C>G
LRG_427p1:p.Gln3239Glu
LRG_427p2:p.Gln3246Glu
NC_000006.11:g.152690199G>C
NM_033071.3:c.9736C>G
NM_182961.2:c.9715C>G

Protein change:

Q3239E

Links:

dbSNP: rs149901087

NCBI 1000 Genomes Browser:

rs149901087

Molecular consequence:

NM_033071.5:c.9736C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_182961.4:c.9715C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000334407	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely benign (Apr 4, 2017)	germline	clinical testing	Citation Link,
SCV000615697	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Likely benign (Apr 14, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001159650	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Oct 5, 2018)	germline	clinical testing	Citation Link,
SCV004813311	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Feb 16, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34890876, 35595401 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	7	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

WARS2 mutations cause dopa-responsive early-onset parkinsonism and progressive myoclonus ataxia.

Skorvanek M, Rektorova I, Mandemakers W, Wagner M, Steinfeld R, Orec L, Han V, Pavelekova P, Lackova A, Kulcsarova K, Ostrozovicova M, Gdovinova Z, Plecko B, Brunet T, Berutti R, Kuipers DJS, Boumeester V, Havrankova P, Tijssen MAJ, Kaiyrzhanov R, Rizig M, Houlden H, et al.

Parkinsonism Relat Disord. 2022 Jan;94:54-61. doi: 10.1016/j.parkreldis.2021.11.030. Epub 2021 Dec 2.

PubMed [citation]

PMID:: 34890876

See all PubMed Citations (3)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000334407.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	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		7	not provided	not provided	not provided

From Athena Diagnostics, SCV000615697.3

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001159650.1

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

Description

The SYNE1: p.Gln3246Glu variant (rs149901087) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a population frequency of 0.6 percent in the Ashkenazi Jewish population (identified on 62 out of 10,152 chromosomes) and has been reported to the ClinVar database (Variation ID: 282775). The glutamine at position 3246 is moderately conserved and computational analyses of the p.Gln3246Glu variant on protein structure and function provide conflicting results (SIFT: tolerated, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Gln3246Glu variant with certainty.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813311.1

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

Description

Variant summary: SYNE1 c.9736C>G (p.Gln3246Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 251296 control chromosomes. c.9736C>G has been reported in the literature as a VUS in a homozygous individual of consanguineous background affected with Spinocerebellar ataxia, autosomal recessive 8 with cerebellar-plus syndrome who carried another homozygous pathogenic variant c.SYNE1 c.16177-2A>G (e.g. Arias_2022). This provides supporting evidence for a benign role of the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35595401, 34890876). ClinVar contains an entry for this variant (Variation ID: 282775). Based on the evidence outlined above, the variant was classified as likely benign.

#	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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