Hypertrophic cardiomyopathy

Gene: SVIL

Comment on publications: PMID:36778260 is a preprint of PMID:39966646

Created: 26 Nov 2025, 12:30 p.m. | Last Modified: 26 Nov 2025, 12:30 p.m.

Panel Version: 5.16

I don't know

Comment on list classification: The main piece of evidence for this gene-disease association is a GWAS study, with no clinical details and limited co-segregation evidence (PMID: 39966646). There are no other cases reported with Hypertrophic cardiomyopathy and heterozygous variants in SVIL. Individuals homozygous for nonsense variants in SVIL have been reported, but the myopathy presentation includes very mild to no cardiac involvement (PMID: 32779703). Based on available evidence, this gene should be rated Amber for Hypertrophic cardiomyopathy, until more evidence emerges.

Created: 24 Nov 2025, 1:58 p.m. | Last Modified: 24 Nov 2025, 1:59 p.m.

Panel Version: 5.12

PMID: 36778260 (2023 pre-print) / PMID: 39966646 Tadros et al., 2025 (published)
GWAS study suggesting rare truncating SVIL variants are associated with high risk of hypertrophic cardiomyopathy. 8 individuals from the HCM cohort were found to carry heterozygous nonsense variants in SVIL. Numerous other rare nonsense variants in SVIL were also reported in the non-HCM control cohort (see supplementary table 19).
Limited evidence of segregation: variant SVIL:p.(Arg1616Ter) was carried by two siblings with HCM; variant SVIL:p.(Gln255Ter) was carried by two cousins with HCM in another family.

PMID: 32779703 Hedberg-Oldfors et al., 2020
Report of 2 unrelated consanguineous families with myopathy with myofibrillar disorganization, homozygous for truncating variants in SVIL. Very mild cardiac involvement: Slightly hypertrophic left ventricular wall 2/4, slight tricuspid regurgitation 2/4; Increased basal wall thickness (30mm) in Individual 1 - noted on cardiac MRI at age 27.

Functional evidence:
PMID: 25633252 Deo et al., 2014: Morpholino knockdown of SVIL causes cardiac edema as well as noticeable spinal curvature at higher morhpolino doses.

The pLI score for SVIL is 0.12, LOEUF = 0.48 - no strong prediction of dosage sensitivity.
This gene is only associated with AR Myofibrillar myopathy 10, 619040 in OMIM (accessed 24th Nov 2025).

Created: 24 Nov 2025, 1:40 p.m. | Last Modified: 24 Nov 2025, 1:54 p.m.

Panel Version: 5.12

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

Phenotypes
hypertrophic cardiomyopathy, MONDO:0005045

Publications

• 36778260
• 39966646

I don't know

In the novel paper described:"the excess burden is even greater at 15.3-fold (95% CI: 5.7-41.3; P:7x10−7) when restricting the analysis to high confidence LoF variants affecting the predominant SVIL transcript in LV (ENST00000375400) (Supplementary Table 6b). In one family, the SVIL LoF variant (p.(Gln255*)) was carried by two cousins with HCM (parents deceased), providing some evidence of co-segregation. Taken together, these data support SVIL as a novel HCM disease gene."
Strong statistical evidence + one family segregating.
Sources: Literature

Created: 30 Apr 2024, 9:27 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
HCM

Publications

• PMID: 36778260