Congenital myopathy

Gene: SRPK3

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 11 Dec 2025, 5:32 p.m. | Last Modified: 11 Dec 2025, 5:32 p.m.

Panel Version: 6.43

Green List (high evidence)

multiple families have now been reported with digenic, pathogenic variants in SRPK3 and TTN genes leading to a progressive early onset skeletal muscle myopathy. All affected patients carry the pathogenic variants in SPRK3 and TTN in combination, and individuals carrying these variants in isolation were not affected by congenital myopathy. Individuals with the single pathogenic TTN variant may be at risk of cardiomyopathy, but not affected by a form of skeletal myopathy in absence of the SRPK3 variant. Analysis of SRPK3 in the the congenital myopathy panel is key to identify affected individuals by this form of digenic form of skeletal myopathy.

Created: 16 Jul 2025, 8:42 a.m. | Last Modified: 16 Jul 2025, 8:42 a.m.

Panel Version: 6.34

Mode of inheritance
Other

Phenotypes
congenital myopathy

Publications

• PMID: 38429495
• PMID: 39667923

Mode of pathogenicity
Other

Comment on list classification: Upgraded from Red to Amber to show that there is sufficient evidence to support this gene-disease association, however, the current GMS Rare Disease bioinformatic pipeline does not allow for interpretation of digenic events and therefore this gene cannot be added to the panel as Green (no evidence for monogenic association).

Created: 4 Aug 2025, 1:08 p.m. | Last Modified: 4 Aug 2025, 1:09 p.m.

Panel Version: 6.35

Comment on list classification: There is no evidence that monogenic variants in this gene cause myopathy. Digenic inheritance is not currently accommodated in tiering. The TTN gene is already included on this panel as Green meaning cases could still be picked up if a TTN variant is present. As this is digenic, this gene has been made Red and tagged 'digenic'.

Created: 19 Jun 2025, 12:54 p.m. | Last Modified: 19 Jun 2025, 12:54 p.m.

Panel Version: 6.8

Based on the Srpk3-null mouse phenotype, which resembles human centronuclear myopathy (PMID:16140986), Töpf et al. 2024 (PMID: 38429495) analysed exome datasets from patients with neuromuscular disease for deleterious variants in the SRPK3 gene. They identified 35 affected individuals from 25 families. Main phenotype is most cases comprised early-onset myopathy and muscle weakness.

Two families displayed dilated cardiomyopathy, associated with a dominantly inherited heterozygous truncating variant in TTN. Authors noted that the myopathic phenotype in these families only manifested when SRPK3 and TTN variants were found in combination, indicating digenic inheritance. The cooccurrence of SRPK3 and TTN variants was then assessed in the remaining cohort, and replicated in all index cases.

Segregation analysis was done in 20 families, showing that in most cases SRPK3 variants were inherited from an unaffected mother and were present in all affected male siblings, with exception of 7 families where variants did not cosegregate with the disease in 9 unaffected male carriers.

Similar results were found by Sharkova et al. 2025 (PMID: 39667923) who report two sibs with prenatal onset muscular dystrophy and digenic variants in the SRPK3 and TTN gene. Myopathy was not present in individuals who carried the SRPK3 but not the TTN variant.

No reports of intellectual impairment or neurological involvement similar to other reports (PMID: 36993381; 39073169) was found across the 26 myopathic families.

Created: 19 Jun 2025, 12:46 p.m. | Last Modified: 19 Jun 2025, 12:46 p.m.

Panel Version: 6.4

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Publications

• 16140986
• 38429495
• 39667923

Green List (high evidence)

multiple cases with: "that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene."

Created: 24 Aug 2024, 1:21 p.m. | Last Modified: 24 Aug 2024, 1:21 p.m.

Panel Version: 4.39

Mode of inheritance
Other

Phenotypes
myopathy

Publications

• 38429495

Red List (low evidence)

SRPK3 is not associated with any phenotypes on OMIM or Gene2Phenotype. There does not apepar to be any published human cases of variants in SRPK3 causing congenital myopathy. There are mouse models (GOF and LOF) (PMID: 16140986).

Created: 8 Aug 2019, 10:02 a.m. | Last Modified: 8 Aug 2019, 10:02 a.m.

Panel Version: 1.155

I don't know

Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26799446 is incorrect. The original file from London South GLH correctly associates PMID: 26799446 to the gene RYR1, but for SRPK3 the publication field was blank (no data was supplied as evidence). The Green review rating for SRPK3 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.

Created: 16 Oct 2019, 3:23 p.m. | Last Modified: 16 Oct 2019, 3:33 p.m.

Panel Version: 1.166

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
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Nemaline myopathy

Publications

• 26799446

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