DDG2P
STR: DMPK_CTG Green List (high evidence)Green List (high evidence)
The DDG2P confidence category for the disease DYSTROPHIA MYOTONICA TYPE 1, OMIM:160900 is definitive. The allelic requirement and mutation consequence are monoallelic_autosomal and altered gene product structure.
The disease-causing mechanism is an amplified trinucleotide CTG repeat in the 3'UTR, rather than SNVs within the gene. As the evidence level for this expansion is high (it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1), and as DDG2P is a component of the Paediatric disorders super panel, the DMPK_CTG STR should be promoted to Green in this panel to ensure that cases are detected.Created: 9 Oct 2023, 7:03 p.m. | Last Modified: 9 Oct 2023, 7:03 p.m.
Panel Version: 3.72
Removed the Q3_21_rating and Q3_21_expert_review tags because this STR is green on other component panels of the Paediatric disorders superpanel and so does not need to be green here.Created: 17 May 2023, 4:20 p.m. | Last Modified: 17 May 2023, 4:20 p.m.
Panel Version: 3.2
STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.Created: 15 Mar 2022, 12:55 p.m. | Last Modified: 15 Mar 2022, 12:55 p.m.
Panel Version: 2.65
Comment on list classification: The genetic defect is an amplified trinucleotide CTG repeat in the 3'UTR (normal range: 5–37; pathological: >50–>2000). Evidence level for this is high - it is a confirmed DD gene for DYSTROPHIA MYOTONICA TYPE 1). As DDG2P is a component of the Paediatric disorders super panel, the DMPK gene was demoted and this STR was added to ensure that cases are appropriately captured.
Only relevant in a paediatric setting if it is a large expansion. A small expansion has adult onset and would be an incidental finding. Therefore, this STR will be flagged for GMS expert review to determine the appropriate 'pathogenic number of repeats' relevant to this panel.Created: 9 Jul 2021, 12:54 p.m. | Last Modified: 9 Jul 2021, 12:57 p.m.
Panel Version: 2.37
Green List (high evidence)
STR added as part of the GMS. This STR is tested routinely using PCR-based methods in the NHS.
Sources: Expert listCreated: 8 Nov 2019, 3:38 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Myotonic dystrophy 1, 16090
Publications
Str: dmpk_ctg has been classified as Green List (High Evidence).
Str: dmpk_ctg has been classified as Green List (High Evidence).
Str: dmpk_ctg has been classified as Green List (High Evidence).
Tag Q3_21_rating was removed from STR: DMPK_CTG. Tag Q3_21_expert_review was removed from STR: DMPK_CTG.
Normal Number of Repeats for DMPK_CTG was changed from 38 to 35. Source NHS GMS was added to STR: DMPK_CTG.
Tag STR tag was added to STR: DMPK_CTG. Tag Q3_21_rating tag was added to STR: DMPK_CTG. Tag Q3_21_expert_review tag was added to STR: DMPK_CTG.
Str: dmpk_ctg has been classified as Amber List (Moderate Evidence).
STR: DMPK_CTG was added STR: DMPK_CTG was added to DDG2P. Sources: Expert Review Green,Expert list Mode of inheritance for STR: DMPK_CTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: DMPK_CTG were set to 7825566 Phenotypes for STR: DMPK_CTG were set to Myotonic dystrophy 1, OMIM:160900
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.