Submission Details

FHOD3 was first reported in relation to autosomal dominant hypertrophic cardiomyopathy in 2018 (Ochoa et al., PMID: 30442288). Over 50 variants (missense, nonsense, splice variants and in frame del/dup variants) that have been reported in over 100 probands in 6 publications (PMIDs: 29907873, 30442288, 30898215, 31742804, 32335906, 33586461) are included in this curation. The majority of variants are located at exon 12 and exon 15, including two recurring variants p.Ser527del and p.Tyr528Cys in exon 12. Most reported variants are missense with a smaller number of truncating, CNV and splice variants identified at these locations. Two CNVs were too large to be registered, an 11kb deletion from c.1836-1527 in intron 14 to c.2022-2042 in intron 16 and an 11kb deletion c.1836-2543 in intron 14 to c.2021+2217 in intron 16, but contribute 0.25 points each to the overall score (Ochoa JP, et al., 2020, PMID: 32335906). The mechanism of pathogenicity is unknown. This gene-disease relationship is also supported by expression studies, protein interaction, functional alteration and animal models (PMIDs: 15966898, 19706596, 29158260, 29686099, 23213483). However, it should be noted that while experimental studies have shown an important role for FHOD3 in heart and sarcomeric development, no studies have demonstrated a clear HCM phenotype. In summary, there is definitive evidence supporting the relationship between FHOD3 and autosomal dominant hypertrophic cardiomyopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Hereditary Cardiovascular Diseases GCEP on the meeting date September 29, 2023 (SOP Version 9).