Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV001807864 | SCV002557435 | pathogenic | Rauch-Steindl syndrome | 2022-06-24 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Rauch-Steindl syndrome (MIM#619695). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0208 - Variant is predicted to result in an elongated protein. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (8 heterozygotes, 0 homozygotes). However, several of these entries have questionable quality. (SP) 0309 - An alternative elongation variant in the same region (p.(Glu1344Argfs*91)) has been observed in gnomAD (v2) (219 heterozygotes, 0 homozygotes). However, this entry has questionable quality. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0708 - Other elongation variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. One comparable variant with a different reading frame to our variant (p.(Glu1344Argfs*91)), has been reported as likely benign (ClinVar). Another comparable variant (p.(Glu1344Lysfs*49)) with the same reading frame as our variant has been reported as de novo and pathogenic, in an individual with atypical Wolf Hirschhorn syndrome (LOVD, PMID: 31382906). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been described as likely pathogenic and de novo in at least two unrelated individuals with features including developmental delay, failure to thrive, dysmorphism and/or motor and speech delay (LOVD, DECIPHER, PMID: 33941880). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Fulgent Genetics, |
RCV001807864 | SCV005662111 | likely pathogenic | Rauch-Steindl syndrome | 2024-03-13 | criteria provided, single submitter | clinical testing | |
| Clinical Genomics Laboratory, |
RCV001807864 | SCV005685525 | likely pathogenic | Rauch-Steindl syndrome | 2024-11-27 | criteria provided, single submitter | clinical testing | The NSD2 c.4028del (p.Pro1343Glnfs*49) variant has been reported in at least four individuals affected with Rauch-Steindl syndrome, three of which were confirmed de novo (Nishi E et al., PMID: 38353053; McConkey H et al., PMID: 36589751; Zanoni P et al., PMID: 33941880). One individual with this variant was positive for the Wolf-Hirschhorn Syndrome episignature that supported their Ruach-Steindl syndrome diagnosis (McConkey H et al., PMID: 36589751). This variant causes a frameshift by deleting a single nucleotide, leading to a premature termination codon; however, because this occurs in the last exon, this is less likely to lead to nonsense mediated decay. This variant is observed on 21/1,601,338 alleles in the general population (gnomAD v.4.1.0). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. |
| OMIM | RCV001807864 | SCV002058103 | pathogenic | Rauch-Steindl syndrome | 2022-01-11 | no assertion criteria provided | literature only |