NM_173660.5(DOK7):c.1124_1127dup (p.Ala378fs) AND Congenital myasthenic syndrome 10

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Sep 27, 2022
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:: RCV000001335.21

Allele description [Variation Report for NM_173660.5(DOK7):c.1124_1127dup (p.Ala378fs)]

NM_173660.5(DOK7):c.1124_1127dup (p.Ala378fs)

Gene:

DOK7:docking protein 7 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

4p16.3

Genomic location:

Preferred name:

NM_173660.5(DOK7):c.1124_1127dup (p.Ala378fs)

Other names:

p.Ala378SerfsX30; p.Ala378Serfs*30

HGVS:

NC_000004.11:g.3494837_3494840dup
NC_000004.12:g.3493110_3493113dup
NG_013072.2:g.34805_34808dup
NM_001164673.2:c.*345_*348dup
NM_001256896.2:c.194_197dup
NM_001301071.2:c.1124_1127dup
NM_001363811.2:c.692_695dup
NM_173660.5:c.1124_1127dupMANE SELECT
NP_001243825.1:p.Ala68fs
NP_001288000.1:p.Ala378fs
NP_001350740.1:p.Ala234fs
NP_775931.3:p.Ala378fs
LRG_869t1:c.1124_1127dup
LRG_869:g.34805_34808dup
LRG_869p1:p.Ala378fs
NC_000004.11:g.3494833_3494834insGCCT
NC_000004.11:g.3494837_3494840dup
NC_000004.11:g.3494837_3494840dupTGCC
NC_000004.11:g.3494837_3494840dupTGCC
NC_000004.11:g.3494840_3494841insTGCC
NC_000004.12:g.3493106_3493107insGCCT
NC_000004.12:g.3493113_3493114insTGCC
NM_001301071.1:c.1124_1127dup
NM_001301071.2:c.1124_1127dup
NM_173660.4:c.1124_1127dupTGCC
NM_173660.5:c.1120_1121insGCCTMANE SELECT
NM_173660.5:c.1124_1127dupTGCCMANE SELECT
NP_775931.3:p.Ala378SerfsTer30

Protein change:

A234fs

Links:

OMIM: 610285.0001; dbSNP: rs606231128

NCBI 1000 Genomes Browser:

rs606231128

Molecular consequence:

NM_001164673.2:c.*345_*348dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001256896.2:c.194_197dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001301071.2:c.1124_1127dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363811.2:c.692_695dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_173660.5:c.1124_1127dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Congenital myasthenic syndrome 10
Synonyms:: Myasthenia, limb-girdle, familial
Identifiers:: MONDO: MONDO:0009690; MedGen: C1850792; Orphanet: 590; OMIM: 254300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000021485	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 2008)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 16917026, 18626973
SCV000247195	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 2, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001162966	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001429333	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 25, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002519580	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV002578149	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin See additional submitters CUBI - Core Unit Bioinformatics, Berlin Institute of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002768618	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 21, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16917026, 18626973, 29054425, 25741868
SCV004048461	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Dok-7 mutations underlie a neuromuscular junction synaptopathy.

Beeson D, Higuchi O, Palace J, Cossins J, Spearman H, Maxwell S, Newsom-Davis J, Burke G, Fawcett P, Motomura M, Müller JS, Lochmüller H, Slater C, Vincent A, Yamanashi Y.

Science. 2006 Sep 29;313(5795):1975-8. Epub 2006 Aug 17.

PubMed [citation]

PMID:: 16917026

Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients.

Selcen D, Milone M, Shen XM, Harper CM, Stans AA, Wieben ED, Engel AG.

Ann Neurol. 2008 Jul;64(1):71-87. doi: 10.1002/ana.21408.

PubMed [citation]

PMID:: 18626973
PMCID:: PMC2570015

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000021485.3

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

Description

In 16 of 21 probands with congenital myasthenic syndrome-10 (CMS10; 254300), Beeson et al. (2006) found homozygosity or compound heterozygosity for a 4-bp duplication between nucleotides 1124 and 1127 in exon 7 of the DOK7 gene, a duplication of TGCC (1124_1127dupTGCC). This frameshift resulted in a premature termination 30 basepairs further downstream (Pro376ProfsTer30). Analysis of acetylcholine receptor clusters from CTC12 myotubes with the mutant DOK7 showed a significant reduction in the number of branched-type plaques, suggesting that the mutation attenuates the maturation of the synaptic structure.

Selcen et al. (2008) identified the 4-bp duplication in 14 of 16 patients with congenital myasthenic syndrome. One patient was homozygous for the mutation, whereas the others were compound heterozygous with another pathogenic DOK7 mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000247195.1

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

From Baylor Genetics, SCV001162966.1

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429333.1

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

Description

This variant was identified as homozygous

#	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		1	not provided	not provided	not provided

From Mendelics, SCV002519580.1

#	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

From Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, SCV002578149.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	germline	yes	1	Blood	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768618.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

A homozygous frameshift duplication variant was identified, NM_173660.4(DOK7):c.1124_1127dup in exon 7 of 7 of the DOK7 gene (NB: This variant is non-coding in an alternative transcript). This duplication is predicted to cause a frameshift starting at position 378 (NP_775931.3(DOK7):p.(Ala378Serfs*30)), resulting in a loss of normal protein function through truncation (including 2 of 4 important tyrosine residues (Selcen, D. et al. (2008))). The variant is present in the gnomAD population database at a frequency of 0.07% (158 heterozygotes; 1 homozygote). The variant has previously been reported as pathogenic in homozygous and compound heterozygous state, in patients with congenital myasthenic syndrome (ClinVar, Beeson, D. et al. (2006), Selcen, D. et al. (2008), Natera-de Benito, D. et al. (2017)). In addition, functional studies showed that this variant causes impaired protein function, affecting the neuromuscular junction (Beeson, D. et al. (2006)). Other variants predicted to cause a truncated protein have been reported as pathogenic in individuals with this condition (ClinVar). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. NB: Transcript NM_173660.4 was chosen for analysis because it is the most clinically relevant isoform and the impact of the variant is predicted to be the most deleterious to the protein. However, in another transcript of this gene this variant is non-coding.

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV004048461.1

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

Description

The frameshift DOK7 (p.Ala378SerfsTer30) variant is one of the most commonly reported mutations among individuals affected with congenital myasthenic syndrome (Beeson D. et. al., 2006; Lashley D et. al., 2010). Experimental studies have shown that this variant affects the phosphorylation of MuSK and also affects the ability of DOK7 protein to produce properly formed AChR clusters (Beeson D. et. al., 2006; Skalak R. et. al., 1990). Additionally, a knock-in mouse model of this variant showed severe muscle weakness (Arimura S. et. al., 2014). This variant has been reported previously in heterozygous state in patients affected with Myasthenic syndrome, congenital,10 (Engel A. G. et. al., 2015; Beeson D. et. al., 2006). The p.Ala378SerfsTer30 variant is novel (not in any individuals) in 1000 Genomes and has an allele frequency of 0.08% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Alanine 378, changes this amino acid to Serine residue, and creates a premature stop codon at position 30 of the new reading frame, denoted p.Ala378SerfsTer30. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 12, 2024

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