Clinical Validity Scoring Notes and points | Variant/Case Evidence: NM_001130021.3:c.2219G>A, NP_001123493.1:p.Arg740Gln Patient 1, PMID: 33833240: De novo, trio exome. 24yo female w/ developmental delay, profound ID, intractable seizures, abnormal EEG. Patient 2, PMID: 33833240: Mot maternally inherited, father deceased. Identified on exome. 15 yo M with developmental delay, profound ID, intractable seizures, abnormal EEG. Patient V.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Male with Infantile spasms; Lip smacking, epilepsy/EEG, ID/DD, Microcephaly, skull and brain asymmetry, Plagiocephaly, scoliosis. Onset of symptoms 11 months. Patient VI.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Female with seizures, ID/DD/ ataxia, myoclonus, prognathism. Onset of symptoms 12 months. Patient VII.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Female with Epilepsy/EEG abnormalities, DD, ataxia. Onset of symptoms 5 months. Patient VIII.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Female with Abnormal hand movements, epilepsy/EEG abnormalities, ID/DD, ataxia, Microcephaly, Severe dystonia. Onset of symptoms 2 months. Patient IX.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Female with epilepsy/EEG abnormalities, ID/DD, ataxia, Microcephaly, Micrognathia, bitemporal narrowing, Optic atrophy. Onset of symptoms 2 months. Patient P:X.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Female with epilepsy/EEG abnormalities, ID/DD, ataxia, myoclonus, Asymmetric volume loss throughout the left hemisphere on brain MRI. Onset of symptoms 6 months. Patient P:XI.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Male with epilepsy/EEG abnormalities, ID/DD, ataxia, microcephaly. Onset of symptoms 3 months. Patient P:XII.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Male with epilepsy/EEG abnormalities, ID/DD, Cerebral and cerebellar atrophy on brain MRI. Onset of symptoms 3 days. PMID: 28135719: Two cases from the Deciphering Developmental Disorders project carried this variant, de novo in both patients. Functional data, PMID: 33833240: Elevated lysosomal pH compared to WT in HEK293FT cell lines (Fig 3). Mouse lines with this variant had no notable abnormalities when the variant was in the heterozygous state but no homozygous pups were born. Authors predicted this variant caused LOF. Further functional studies in cell lines - PMID: 34909687. REVEL: 0.959. Absent from gnomAD v4. P/LP in ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/variation/560227/ Scoring: (missense (0.1)+ de novo (0.5)) * 10 occurrences + functional data (0.5) = 6.5 points
NM_001130021.3:c.1429T>C, NP_001123493.1:p.Ser477Pro Patient III.1, PMID: 34909687: De novo, identified on exome and segregated via Sanger. Male with hypotonia, developmental delay, scoliosis, pectus carinatum, laryngomalacia (no epilepsy/EEG abnormalities). Onset of symptoms 4 months. REVEL: 0.934. Absent from gnomAD v4. P in ClinVar by OMIM: https://www.ncbi.nlm.nih.gov/clinvar/variation/1698401/ Scoring: 0 points, patient did not have epilepsy.
NM_001130021.3:c.1652G>A, NP_001123493.1:p.Gly551Glu Patient IV.1, PMID: 34909687: De novo, identified on exome and segregated via Sanger. Male with developmental delay, Epilepsy/EEG abnormalities, ID, White-matter gliosis on brain MRI, Amelogenesis imperfecta, clubfoot. Onset of symptoms 7 months. REVEL: 0.933. Absent from gnomAD v4. Not in ClinVar. Scoring: missense (0.1) + de novo (0.5) = 0.6 points
NM_001130021.3:c.2411G>A, NP_001123493.1:p.Arg804His Patient XIII.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Male with ID/DD, Microcephaly, simplified gyration, Prognathism. Onset of symptoms at 12 months. Patient XIV.1, PMID: 34909687: De novo, variant identified on exome and segregated via Sanger. Stillborn female with Micrognathia, hypertelorism. REVEL: 0.975. Absent from gnomAD v4. P in ClinVar by OMIM: https://www.ncbi.nlm.nih.gov/clinvar/variation/1698403/ Scoring: 0 points, patient did not have epilepsy.
Segregation Evidence: N/A Case/Control Evidence: N/A Experimental Evidence: N/A Source: PMID: 33833240, 34909687 |
Curation Summary Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited | ATP6V0A1 is associated with autosomal dominant developmental and epileptic encephalopathy. Individuals with this condition may have epilepsy, developmental delay, intellectual disability, ataxia, and microcephaly. Some individuals have been reported to have brain MRI abnormalities, scoliosis, hypotonia, myoclonus, and dysmorphic features. Although autosomal dominant inheritance appears to be more common, autosomal recessive inheritance has also been reported (PMID: 33833240, 34909687, 37465367). |