Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004790112 | SCV005400088 | likely pathogenic | Congenital contractures of the limbs and face, hypotonia, and developmental delay | 2023-07-16 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (MIM#615419). Dominant negative and gain of function are postulated mechanisms for autosomal dominant congenital contractures of the limbs and face, hypotonia, and developmental delay (MIM# 6162660) (PMID: 26763878). (I) 0108 - This gene is associated with both recessive and dominant disease. The recessive condition is associated with both null variants and missense variants outside of the S5/S6 segments of the protein (PMID: 30167850), whereas the dominant condition is mostly associated with missense variants within the S5/S6 segments (PMID: 26763878). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER), within the S5 segment of the ion transporter domain (PMID: 25683120). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Arg173Gln)) has been reported as likely pathogenic and pathogenic, and observed as de novo in two individuals with features including arthrogryposis, global developmental delay and/or ataxia (VCGS, DECIPHER). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |