VCV000001273.86 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(31)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 1273 Accession: VCV000001273.86

Type and length

Duplication, 4 bp

Location

Cytogenetic: 4p16.3 4: 3493106-3493107 (GRCh38) [ NCBI UCSC ] 4: 3494833-3494834 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 1, 2015	Oct 26, 2024	May 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_173660.5:c.1120_1121insGCCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_173660.5:c.1124_1127dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_775931.3:p.Ala378fs	frameshift
NM_173660.5:c.1124_1127dupTGCC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001164673.2:c.345_348dup		3 prime UTR
NM_001256896.2:c.194_197dup	NP_001243825.1:p.Ala68fs	frameshift
NM_001301071.2:c.1124_1127dup	NP_001288000.1:p.Ala378fs	frameshift
NM_001363811.2:c.692_695dup	NP_001350740.1:p.Ala234fs	frameshift
NC_000004.12:g.3493110_3493113dup
NC_000004.11:g.3494837_3494840dup
NG_013072.2:g.34805_34808dup
LRG_869:g.34805_34808dup
LRG_869t1:c.1124_1127dup	LRG_869p1:p.Ala378fs

... more HGVS ... less HGVS

Protein change

A234fs, A378fs, A68fs

Other names

p.Ala378SerfsX30
p.Ala378Serfs*30

Canonical SPDI

NC_000004.12:3493106:GCCTGCC:GCCTGCCTGCC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA249193 OMIM: 610285.0001 dbSNP: rs606231128 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DOK7		-	-	GRCh38 GRCh37	1107	1337

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital myasthenic syndrome 10	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Sep 27, 2022	RCV000001335.22
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	May 1, 2024	RCV000202989.40
Congenital myasthenic syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 3, 2023	RCV000235027.11
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Apr 27, 2015	RCV000624523.5
Congenital myasthenic syndrome 10 Fetal akinesia deformation sequence 1	Pathogenic (1)	criteria provided, single submitter	Jan 25, 2024	RCV000560473.13
Congenital myasthenic syndrome 10 Fetal akinesia deformation sequence 3	Pathogenic (2)	criteria provided, single submitter	Aug 3, 2021	RCV001535493.6
Abnormality of the musculature	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001813932.4
See cases	Pathogenic (1)	criteria provided, single submitter	Sep 26, 2019	RCV002251852.4
DOK7-related disorder	Pathogenic (1)	no assertion criteria provided	Jan 25, 2024	RCV003398412.6
Fetal akinesia deformation sequence 3	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 27, 2024	RCV003466775.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 02, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myasthenia, limb-girdle, familial Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000247195.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Pathogenic (Apr 14, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Not provided Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000258262.2 First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015
Pathogenic (Nov 23, 2014)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000232357.4 First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019	Publications: PubMed (1) PubMed: 20610155 Other databases http://geneticslab.emory.edu/emv… http://geneticslab.emory.edu/emvclass/emvclass.php?approved_symbol=DOK7 Number of individuals with the variant: 5 Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 10 Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001162966.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Congenital myasthenic syndrome 10 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002519580.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Sep 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 10 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin Additional submitter: CUBI - Core Unit Bioinformatics, Berlin Institute of Health Accession: SCV002578149.1 First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022	Clinical Features: Hypotonia (present) , Waddling gait (present) , Neonatal respiratory distress (present) Sex: male Tissue: Blood
Pathogenic (Aug 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 10 Fetal akinesia deformation sequence 3 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002788931.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Mar 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004025988.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PVS1, PM2_SUP, PS3, PM3
Pathogenic (Nov 03, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Congenital myasthenic syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004223317.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (2) PubMed: 18626973‚ 18165682 Comment: Variant summary: DOK7 c.1124_1127dupTGCC (p.Ala378SerfsX30) results in a premature termination codon affecting the last 127 codons in the last exon of the encoded protein. Although … (more) Variant summary: DOK7 c.1124_1127dupTGCC (p.Ala378SerfsX30) results in a premature termination codon affecting the last 127 codons in the last exon of the encoded protein. Although nonsense mediated decay is not expected to occur, truncations are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00064 in 193594 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in DOK7 causing Congenital Myasthenic Syndrome (0.00064 vs 0.0014), allowing no conclusion about variant significance. c.1124_1127dupTGCC has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Dok-7 myasthenia (e.g. Selcen_2008). These data indicate that the variant is very likely to be associated with disease. One publication reports in vitro experimental evidence evaluating an impact on protein function, however, additional evidence is needed to provide convincing conclusions about the variant effect in vivo (e.g. Hamuro_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18165682, 18626973). 17 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002021748.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Feb 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004243175.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Pathogenic (Jun 29, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004563179.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: The DOK7 c.1124_1127dup; p.Ala378SerfsTer30 variant (rs606231128), is reported in the literature in several homozygous and compound heterozygous individuals affected with congenital myasthenic syndrome (Beeson 2006, … (more) The DOK7 c.1124_1127dup; p.Ala378SerfsTer30 variant (rs606231128), is reported in the literature in several homozygous and compound heterozygous individuals affected with congenital myasthenic syndrome (Beeson 2006, Fernandes 2021, Lorenzoni 2020), and is the most common pathogenic variant detected in DOK7 (Lorenzoni 2020). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 1273). This variant is found in the non-Finnish European population with an allele frequency of 0.12% (119/99,632 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by inserting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Beeson et al. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science. 2006 Sep 29;313(5795):1975-8. PMID: 16917026. Fernandes M et al. Diagnosis of DOK7 congenital myasthenic syndrome during pregnancy: A case report and literature review. Clin Neurol Neurosurg. 2021 Apr;203:106591. PMID: 33714798. Lorenzoni PJ et al. Congenital myasthenic syndrome due to DOK7 mutation in a cohort of patients with 'unexplained' limb-girdle muscular weakness. J Clin Neurosci. 2020 May;75:195-198. PMID: 32238315. (less)
Pathogenic (Mar 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711740.2 First in ClinVar: Jul 19, 2016 Last updated: Apr 20, 2024	Publications: PubMed (4) PubMed: 19261599‚ 16917026‚ 25237101‚ 23790237 Comment: The p.Ala378SerfsX30 variant in DOK7 has been reported in the homozygous or compound heterozygous state in >10 individuals with congenital myasthenic syndrome (Beeson 2006 PMID: … (more) The p.Ala378SerfsX30 variant in DOK7 has been reported in the homozygous or compound heterozygous state in >10 individuals with congenital myasthenic syndrome (Beeson 2006 PMID: 16917026, Lorenzoni 2013 PMID: 23790237). It has also been identified in 0.12% (119/99632) of European (non-Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID: 1273). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 378 and leads to a premature termination codon 30 amino acids downstream. This termination codon occurs within the last exon and is likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies suggest that this truncation impacts protein function (Beeson 2006 PMID: 16917026). Additionally, mouse knock-in models support a disease-causing role (Arimura 2014 PMID: 25237101). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital myasthenic syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PS3, PM3_Strong. (less)
Pathogenic (Apr 13, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000613161.1 First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015	Publications: PubMed (17) PubMed: 16917026‚ 17452375‚ 19837590‚ 18626973‚ 17439981‚ 20610155‚ 20562457‚ 18161030‚ 18165682‚ 20012313‚ 26583494‚ 23657916‚ 22661499‚ 25033858‚ 27391121‚ 25326637‚ 20554332
Pathogenic (Feb 25, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 10 Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429333.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Comment: This variant was identified as homozygous Number of individuals with the variant: 1
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the musculature Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755389.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Sep 26, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523260.1 First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022	Comment: ACMG classification criteria: PVS1, PS3, PM3 Clinical Features: Short stature (present) , Peripheral neuropathy (present) , Generalized hypotonia (present) , Cerebellar ataxia (present) , Movement disorder (present) Geographic origin: Brazil
Pathogenic (May 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 10 Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768618.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 16917026‚ 18626973‚ 29054425 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 27, 2015)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741119.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (4) PubMed: 22661499‚ 16917026‚ 23657916‚ 21041412 Observation 1: Number of individuals with the variant: 1 Clinical Features: Muscular hypotonia (present) , Sensorimotor neuropathy (present) , Global developmental delay (present) , Growth delay (present) , Reduced tendon reflexes (present) Sex: female Observation 2: Number of individuals with the variant: 1 Clinical Features: Muscle weakness (present) , Increased adipose tissue (present) , Increased body weight (present) , Obesity (present) , Constipation (present) , Alopecia (present) , Myopathy (present) … (more) Muscle weakness (present) , Increased adipose tissue (present) , Increased body weight (present) , Obesity (present) , Constipation (present) , Alopecia (present) , Myopathy (present) , Generalized muscle weakness (present) , Thoracic scoliosis (present) , Pes planus (present) , Ptosis (present) , Scoliosis (present) , Nevus (present) , Areflexia (present) , Gait disturbance (present) , Hyperlordosis (present) , Waddling gait (present) , Lower limb pain (present) , Ankle contracture (present) , Generalized hypotonia (present) , Decreased muscle mass (present) , Decreased pulmonary function (present) , Easy fatigability (present) (less) Sex: male Ethnicity/Population group: African American
Pathogenic (May 16, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567740.6 First in ClinVar: Dec 27, 2015 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate that this variant impairs activity and its ability to induce AChR clustering (Beeson et al., 2006; Cossins et al., 2012); Frameshift … (more) Published functional studies demonstrate that this variant impairs activity and its ability to induce AChR clustering (Beeson et al., 2006; Cossins et al., 2012); Frameshift variant predicted to result in protein truncation, as the last 127 amino acids are replaced with 29 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 26501342, 29395672, 29315608, 18626973, 32403337, 18161030, 30487145, 22661499, 26583494, 29054425, 29118959, 23657916, 33726816, 31453852, 32238315, 31447096, 30609409, 31127727, 31980526, 34103343, 34426522, 32528171, 33146414, 16917026) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 10 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004048461.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: 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; … (more) 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. (less) Clinical Features: Gait disturbance (present) , Frequent falls (present) , Limb muscle weakness (present) , Myopathy (present)
Pathogenic (Dec 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226080.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: PP1, PP5, PM3, PS3, PS4, PVS1_strong Number of individuals with the variant: 2
Pathogenic (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Congenital myasthenic syndrome 10 Fetal akinesia deformation sequence 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000640935.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (12) PubMed: 28492532‚ 16917026‚ 17452375‚ 18626973‚ 20012313‚ 20458068‚ 22661499‚ 23219351‚ 23790237‚ 2261499‚ 18165682‚ 25237101 Comment: This sequence change creates a premature translational stop signal (p.Ala378Serfs30) in the DOK7 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Ala378Serfs30) in the DOK7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 127 amino acid(s) of the DOK7 protein. This variant is present in population databases (rs764365793, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with congenital myasthenic syndrome (PMID: 16917026, 17452375, 18626973, 20012313, 20458068, 22661499, 23219351, 23790237). ClinVar contains an entry for this variant (Variation ID: 1273). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DOK7 function (PMID: 2261499, 16917026, 18165682, 18626973, 25237101). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fetal akinesia deformation sequence 3 Affected status: no Allele origin: unknown	Genomic Medicine Lab, University of California San Francisco Accession: SCV004847137.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fetal akinesia deformation sequence 3 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004194013.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (May 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247240.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: DOK7: PM3:Very Strong, PP1:Strong, PVS1:Strong, PM2, PP4 Number of individuals with the variant: 7
Pathogenic (Jul 01, 2008)	no assertion criteria provided Method: literature only	MYASTHENIC SYNDROME, CONGENITAL, 10 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021485.3 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2015	Publications: PubMed (2) PubMed: 16917026‚ 18626973 Comment on evidence: 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 … (more) 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. (less)
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Fetal akinesia deformation sequence 3 Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005200043.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team
Pathogenic (Jan 25, 2024)	no assertion criteria provided Method: clinical testing	DOK7-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104232.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The DOK7 c.1124_1127dupTGCC variant is predicted to result in a frameshift and premature protein termination (p.Ala378Serfs30). This variant has been reported in many unrelated individuals … (more) The DOK7 c.1124_1127dupTGCC variant is predicted to result in a frameshift and premature protein termination (p.Ala378Serfs30). This variant has been reported in many unrelated individuals to be causative for autosomal recessive congenital myasthenic syndrome (Beeson et al. 2006. PubMed ID: 16917026; Cossins et al. 2012. PubMed ID: 22661499; Natera-de Benito et al. 2017. PubMed ID: 29054425). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in DOK7 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Congenital myasthenic syndrome Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000292401.2 First in ClinVar: Jul 19, 2016 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 22230109‚ 16917026 BookShelf: NBK1168 BookShelf: NBK1168
not provided (-)	no classification provided Method: phenotyping only	Congenital myasthenic syndrome 10 Fetal akinesia deformation sequence 3 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749440.2 First in ClinVar: Jul 18, 2021 Last updated: Jun 17, 2024	Comment: Variant interpreted as Pathogenic and reported on 06-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more) Variant interpreted as Pathogenic and reported on 06-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Myopia (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) Indication for testing: Diagnostic Age: 60-69 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-06-29 Testing laboratory interpretation: Pathogenic
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Comment:

Variant summary: DOK7 c.1124_1127dupTGCC (p.Ala378SerfsX30) results in a premature termination codon affecting the last 127 codons in the last exon of the encoded protein. Although nonsense mediated decay is not expected to occur, truncations are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00064 in 193594 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in DOK7 causing Congenital Myasthenic Syndrome (0.00064 vs 0.0014), allowing no conclusion about variant significance. c.1124_1127dupTGCC has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Dok-7 myasthenia (e.g. Selcen_2008). These data indicate that the variant is very likely to be associated with disease. One publication reports in vitro experimental evidence evaluating an impact on protein function, however, additional evidence is needed to provide convincing conclusions about the variant effect in vivo (e.g. Hamuro_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18165682, 18626973). 17 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The DOK7 c.1124_1127dup; p.Ala378SerfsTer30 variant (rs606231128), is reported in the literature in several homozygous and compound heterozygous individuals affected with congenital myasthenic syndrome (Beeson 2006, Fernandes 2021, Lorenzoni 2020), and is the most common pathogenic variant detected in DOK7 (Lorenzoni 2020). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 1273). This variant is found in the non-Finnish European population with an allele frequency of 0.12% (119/99,632 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by inserting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Beeson et al. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science. 2006 Sep 29;313(5795):1975-8. PMID: 16917026. Fernandes M et al. Diagnosis of DOK7 congenital myasthenic syndrome during pregnancy: A case report and literature review. Clin Neurol Neurosurg. 2021 Apr;203:106591. PMID: 33714798. Lorenzoni PJ et al. Congenital myasthenic syndrome due to DOK7 mutation in a cohort of patients with 'unexplained' limb-girdle muscular weakness. J Clin Neurosci. 2020 May;75:195-198. PMID: 32238315.

Comment:

The p.Ala378SerfsX30 variant in DOK7 has been reported in the homozygous or compound heterozygous state in >10 individuals with congenital myasthenic syndrome (Beeson 2006 PMID: 16917026, Lorenzoni 2013 PMID: 23790237). It has also been identified in 0.12% (119/99632) of European (non-Finnish) chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID: 1273). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 378 and leads to a premature termination codon 30 amino acids downstream. This termination codon occurs within the last exon and is likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies suggest that this truncation impacts protein function (Beeson 2006 PMID: 16917026). Additionally, mouse knock-in models support a disease-causing role (Arimura 2014 PMID: 25237101). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital myasthenic syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PS3, PM3_Strong.

Comment:

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.

Comment:

Published functional studies demonstrate that this variant impairs activity and its ability to induce AChR clustering (Beeson et al., 2006; Cossins et al., 2012); Frameshift variant predicted to result in protein truncation, as the last 127 amino acids are replaced with 29 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 26501342, 29395672, 29315608, 18626973, 32403337, 18161030, 30487145, 22661499, 26583494, 29054425, 29118959, 23657916, 33726816, 31453852, 32238315, 31447096, 30609409, 31127727, 31980526, 34103343, 34426522, 32528171, 33146414, 16917026)

Comment:

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.

Comment:

This sequence change creates a premature translational stop signal (p.Ala378Serfs*30) in the DOK7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 127 amino acid(s) of the DOK7 protein. This variant is present in population databases (rs764365793, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with congenital myasthenic syndrome (PMID: 16917026, 17452375, 18626973, 20012313, 20458068, 22661499, 23219351, 23790237). ClinVar contains an entry for this variant (Variation ID: 1273). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DOK7 function (PMID: 2261499, 16917026, 18165682, 18626973, 25237101). For these reasons, this variant has been classified as Pathogenic.

Comment:

The DOK7 c.1124_1127dupTGCC variant is predicted to result in a frameshift and premature protein termination (p.Ala378Serfs*30). This variant has been reported in many unrelated individuals to be causative for autosomal recessive congenital myasthenic syndrome (Beeson et al. 2006. PubMed ID: 16917026; Cossins et al. 2012. PubMed ID: 22661499; Natera-de Benito et al. 2017. PubMed ID: 29054425). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in DOK7 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 06-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Congenital Myasthenic Syndromes Overview.	Adam MP	-	2021	PMID: 20301347
Molecular characterization of congenital myasthenic syndromes in Spain.	Natera-de Benito D	Neuromuscular disorders : NMD	2017	PMID: 29054425
Whole exome sequencing diagnosis of inborn errors of metabolism and other disorders in United Arab Emirates.	Al-Shamsi A	Orphanet journal of rare diseases	2016	PMID: 27391121
Anticholinesterase Therapy Worsening Head Drop and Limb Weakness Due to a Novel DOK7 Mutation.	Lozowska D	Journal of clinical neuromuscular disease	2015	PMID: 26583494
Clinical exome sequencing for genetic identification of rare Mendelian disorders.	Lee H	JAMA	2014	PMID: 25326637
Neuromuscular disease. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction.	Arimura S	Science (New York, N.Y.)	2014	PMID: 25237101
Familial Dok7 congenital myasthenic syndrome responsive to salbutamol.	Maramattom BV	Neurology India	2014	PMID: 25033858
Salbutamol therapy in congenital myasthenic syndrome due to DOK7 mutation.	Lorenzoni PJ	Journal of the neurological sciences	2013	PMID: 23790237
Congenital myasthenic syndrome and minicore-like myopathy with DOK7 mutation.	Lorenzoni PJ	Muscle & nerve	2013	PMID: 23657916
Salbutamol benefits children with congenital myasthenic syndrome due to DOK7 mutations.	Burke G	Neuromuscular disorders : NMD	2013	PMID: 23219351
The spectrum of mutations that underlie the neuromuscular junction synaptopathy in DOK7 congenital myasthenic syndrome.	Cossins J	Human molecular genetics	2012	PMID: 22661499
186th ENMC international workshop: congenital myasthenic syndromes 24-26 June 2011, Naarden, The Netherlands.	Chaouch A	Neuromuscular disorders : NMD	2012	PMID: 22230109
Dok-7 regulates neuromuscular synapse formation by recruiting Crk and Crk-L.	Hallock PT	Genes & development	2010	PMID: 21041412
DOK7 mutations presenting as a proximal myopathy in French Canadians.	Srour M	Neuromuscular disorders : NMD	2010	PMID: 20610155
Molecular characterisation of congenital myasthenic syndromes in Southern Brazil.	Mihaylova V	Journal of neurology, neurosurgery, and psychiatry	2010	PMID: 20562457
Congenital stridor with feeding difficulty as a presenting symptom of Dok7 congenital myasthenic syndrome.	Jephson CG	International journal of pediatric otorhinolaryngology	2010	PMID: 20554332
Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7.	Lashley D	Neurology	2010	PMID: 20458068
Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7.	Ben Ammar A	Journal of neurology	2010	PMID: 20012313
Ephedrine therapy in eight patients with congenital myasthenic syndrome due to DOK7 mutations.	Schara U	Neuromuscular disorders : NMD	2009	PMID: 19837590
Germline mutation in DOK7 associated with fetal akinesia deformation sequence.	Vogt J	Journal of medical genetics	2009	PMID: 19261599
Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients.	Selcen D	Annals of neurology	2008	PMID: 18626973
Mutations causing DOK7 congenital myasthenia ablate functional motifs in Dok-7.	Hamuro J	The Journal of biological chemistry	2008	PMID: 18165682
Variable phenotypes associated with mutations in DOK7.	Anderson JA	Muscle & nerve	2008	PMID: 18161030
Clinical features of the DOK7 neuromuscular junction synaptopathy.	Palace J	Brain : a journal of neurology	2007	PMID: 17452375
Phenotypical spectrum of DOK7 mutations in congenital myasthenic syndromes.	Müller JS	Brain : a journal of neurology	2007	PMID: 17439981
Dok-7 mutations underlie a neuromuscular junction synaptopathy.	Beeson D	Science (New York, N.Y.)	2006	PMID: 16917026
Rheological aspects of red blood cell aggregation.	Skalak R	Biorheology	1990	PMID: 2261499
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Text-mined citations for rs606231128 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs606231128 ...