Table 2.
Instances of non-penetrance. List of patients who lack the clinical phenotypes predicted by P/LP variants identified by CES/CGS even after careful reverse phenotyping
| ID | Patient phenotype | Gene | NM | Zygosity | Type and classification | OMIM phenotype | Evidence of pathogenicity | Result of reverse phenotyping |
|---|---|---|---|---|---|---|---|---|
| 192LO9459 | Hearing impairment—Male infertility—Chronic sinusitis—Reduced sperm motility—Abnormal sperm morphology | CAPN3 | NM_000070.2:c.1466G > A;p.(Arg489Gln) | Homozygous | Missense Pathogenic (class 1) | Muscular dystrophy, limb-girdle, autosomal recessive 1 (253,600) AR | This variant has been published several times before (PMIDs: 10,330,340, 39,411,402, 31,589,614, 38,523,675, 32,668,095, 14,578,192, 38,324,470, 30,919,934). It is classified as pathogenic based on the criteria: PP5_Strong, PM1_Moderate, PM5_Moderate, PP3_Moderate, PM2_Supporting | Lack of clinical muscle involvement |
| 123LO2080 | Brain atrophy—Cerebellar atrophy—Colpocephaly—Diabetes mellitus—Hypoplasia of the corpus callosum—Increased size of nasopharyngeal adenoids—Intellectual disability—Long nose—Microcephaly—Short philtrum | COL1A1 | NM_000088.3:c.2010del;p.(Gly671Alafs*95) | Heterozygous | Frameshift Pathogenic (class 1) | Osteogenesis imperfecta type I | This variant has been published several times before (PMIDs: 11,317,364, 26,863,094, 32,860,008, 33,939,306, 35,611,912, 31,239,369, 37,270,749, 37,270,749). It has been classified as pathogenic based on the criteria: PVS1_Very Strong, PP5_Very Strong, PM2_Supporting, PMID: 11,317,364 | Lack of clinical and radiological bone involvement |
| 163LO7560 | Abnormality of the eye—Blindness—Congenital onset—Retinal degeneration—Visual impairment | RNASEH2A | NM_006397.2:c.557G > A;p.(Arg186Gln) | Homozygous | Missense Pathogenic (class 2) | Aicardi-Goutieres syndrome | This variant has been published several times (PMIDs: 24,300,241, 29,239,743, 38,976,295, 36,937,954, 38,178,268, 36,705,819, 38,909,119, 36,065,636, 31,130,284 and 34,374,989). It has been classified as pathogenic based on the following criteria: PP5_Very Strong, PP3_Strong, PM5_Moderate and PM2_Supporting | Lack of neurological involvement |