4-3493106-A-AGCCT

Position:

• chr4-3493106-A-AGCCT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_173660.5(DOK7):​c.1124_1127dup​(p.Ala378SerfsTer30) variant causes a frameshift change. The variant allele was found at a frequency of 0.00111 in 1,584,152 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: DOK7 NM_173660.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:29 O:2
• Conservation: PhyloP100: 6.82

Genes affected

DOK7 (HGNC:26594): (docking protein 7) The protein encoded by this gene is essential for neuromuscular synaptogenesis. The protein functions in aneural activation of muscle-specific receptor kinase, which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PP5: Variant 4-3493106-A-AGCCT is Pathogenic according to our data. Variant chr4-3493106-A-AGCCT is described in ClinVar as [Pathogenic]. Clinvar id is 1273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOK7	NM_173660.5	c.1124_1127dup	p.Ala378SerfsTer30	frameshift_variant	7/7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.1124_1127dup	p.Ala378SerfsTer30	frameshift_variant	7/7	1	NM_173660.5	ENSP00000344432	P1
DOK7	ENST00000515886.5	c.194_197dup	p.Ala68SerfsTer30	frameshift_variant	4/4	2		ENSP00000492194
DOK7	ENST00000643608.1	c.692_695dup	p.Ala234SerfsTer30	frameshift_variant	5/8			ENSP00000495701
DOK7	ENST00000507039.5	c.*345_*348dup		3_prime_UTR_variant	7/7	2		ENSP00000423614

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152186 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000635 AC: 123 AN: 193594 Hom.: 1 AF XY: 0.000591 AC XY: 63 AN XY: 106522

Gnomad AFR exome AF: 0.0000913

Gnomad AMR exome AF: 0.000771

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000338

Gnomad FIN exome AF: 0.0000735

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000398

GnomAD4 exome AF: 0.00114 AC: 1637 AN: 1431848 Hom.: 2 Cov.: 112 AF XY: 0.00112 AC XY: 794 AN XY: 710568

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000755

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000819

Gnomad4 FIN exome AF: 0.0000888

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152304 Hom.: 0 Cov.: 34 AF XY: 0.000712 AC XY: 53 AN XY: 74484

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.000676

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 23, 2022	PP1, PP5, PM3, PS3, PS4, PVS1_strong -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DOK7: PM3:Very Strong, PP1:Strong, PVS1:Strong, PM2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Mar 14, 2022	PVS1, PM2_SUP, PS3, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 29, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2022	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) -

Congenital myasthenic syndrome 10 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 25, 2020	This variant was identified as homozygous -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 02, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Fetal akinesia deformation sequence 3 Pathogenic:3

Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Sep 22, 2023	- -

Congenital myasthenic syndrome Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2023	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Congenital myasthenic syndrome 10;C4760599:Fetal akinesia deformation sequence 3 Pathogenic:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 03, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2015

- -

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

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. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Sep 26, 2019

ACMG classification criteria: PVS1, PS3, PM3 -

DOK7-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2024

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. -

Abnormality of the musculature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs606231128; hg19: chr4-3494833;