Congenital muscular dystrophy and congenital myopathy

Gene: CCDC78

I don't know

The rating of this gene has been updated to Amber following NHS Genomic Medicine Service approval. Additional comments from reviewing GLHs: 'Looks like there is only one reported study from 2012. If lab don t have additional cases then demote to Amber. Agree to remain at Amber'

Created: 2 May 2024, 3:45 p.m. | Last Modified: 2 May 2024, 3:45 p.m.

Panel Version: 0.229

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

I don't know

Comment on classification of this gene: The rating for this gene should be changed to AMBER from green, as I believe this gene does not meet the criteria for rating green. This gene has been implicated in congenital myopathy, as identified from monoallelic variants from only one family (the second family showed reduced penetrance) and supported by results from functional studies.

As reported by Majczenko (2012) and noted in other reviews, five affected individuals from one family identified with 222 bp in-frame insertion were reported with a phenotype consistent with congenital myopathy. This variant is not present in unaffected family members. In addition, modelling CCDC78 mutant in zebrafish resulted in changes mirroring the human disease that included altered motor function and abnormal muscle ultrastructure (PMID:22818856).

Although a single individual with an autosomal dominant variant in CCDC78 (c.1133+1G>C) was reported with symptoms associated with congenital myopathy such as muscle weakness from one to two years of age, the mother of the patient carrying the same autosomal dominant variant did not show any symptoms suggesting reduced penetrance of this variant (PMID:25635128).

Tracy Lester also noted that several cases with heterozygous variant p.Arg24Ter were not reported with myopathy in CVA, questioning the association of CCDC78 with congenital myopathy. ClinVar also reports this variant as of uncertain significance.

Although this gene has provisionally been associated with centronuclear myopathy-4 in OMIM, this was only on the basis of the single family reported by Majczenko (2012). In addition, this gene was not associated with any other Panels with a green rating. I would therefore like to flag this gene for additional review by NHS experts.

Created: 11 Dec 2022, 7:35 p.m. | Last Modified: 11 Dec 2022, 7:35 p.m.

Panel Version: 3.1

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
centronuclear myopathy-4, MIM# 614807

Publications

• 22818856
• 25635128

Red List (low evidence)

This gene doesn't meet criteria to be green. Nonsense variant R24* Chr16(GRCh38):g.726076G>A seen het in multiple cases in CVA without myopathy and also in gnomad. Another splice-variant reported in a case with congenital myopathy, but apparently inherited from an unaffected parent (25635128).

Created: 7 Oct 2022, 3:55 p.m. | Last Modified: 7 Oct 2022, 3:55 p.m.

Panel Version: 2.90

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
congenital myopathy

Publications

• 25635128

I don't know

Segregation in one family reported and a zebrafish model with altered motor function and abnormal muscle ultrastructure. Does not meet criteria for Green rating.

Created: 12 Jun 2020, 10:49 a.m. | Last Modified: 12 Jun 2020, 10:49 a.m.

Panel Version: 2.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Myopathy, centronuclear, 4, 614807

Publications

• 22818856

I don't know

As a result of watchlist tag audit the watchlist tag was removed from CCDC78- this is now a green gene.

Created: 13 Jan 2020, 11:42 a.m. | Last Modified: 13 Jan 2020, 11:42 a.m.

Panel Version: 2.0

Comment on list classification: Upgraded rating from Amber to Green. There is only a single family reported, however Anna Sarkozy (Great Ormond Street Hospital) and Francesco Muntoni (Great Ormond Street Hospital) recommend a Green rating for this gene on R81

Created: 5 Dec 2019, 4:32 p.m. | Last Modified: 5 Dec 2019, 4:35 p.m.

Panel Version: 1.225

Remain Amber unless further evidence supplied by GLH

Created: 3 Dec 2019, 2:58 p.m. | Last Modified: 3 Dec 2019, 2:58 p.m.

Panel Version: 1.198

Gene rating and review submitted by Rachael Mein, Viapath Guy's Hospital February 2019 on on behalf of London South GLH for the GMS Neurology specialist test group.

Created: 30 Apr 2019, 10:09 a.m.

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Myopathy, centronuclear, 4, 614807

Publications

• 22818856

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

this can be upgraded to green

Created: 30 May 2019, 4:36 p.m. | Last Modified: 5 Dec 2019, 3:07 p.m.

Panel Version: 1.223

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Myopathy, centronuclear, 4, 614807

Publications

• 22818856

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

Comment on list classification: Expert contacted to see if there are additional cases to the single published to date. Amber and watchlist on current evidence.

Created: 7 Mar 2017, 2:38 p.m.

Comment when marking as ready: One family identified. If further evidence emerges, could be green as phenotype seems to fit.

Created: 3 Feb 2017, 11:44 a.m.

Comment on list classification: Insufficient evidence. One family, although phenotype reported is appropriate.

Created: 3 Feb 2017, 11:42 a.m.

Only one family identified to date (5 affected individuals). Phenotype is consistent with congenital myopathy but currently evidence is insufficient. Mutation in this family is 222bp in-frame insertion.

Created: 30 Jan 2017, 2:29 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Myopathy, centronuclear, 4 614807

Publications

• PMID 22818856

Mode of pathogenicity
Other