Submissions for variant NM_003107.3(SOX4):c.1040C>A (p.Ser347Ter)

dbSNP: rs2113558441

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV001598703	SCV001827227	likely pathogenic	Coffin-Siris syndrome 10	2021-06-18	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001598703	SCV005399837	pathogenic	Coffin-Siris syndrome 10	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a suggested mechanism of disease in this gene and is associated with Coffin-Siris syndrome 10 (MIM#618506). Functional studies in transfected cells expressing both wild type and variant protein showed a significant reduction in wild type protein activity (PMID: 35232796). Other functional studies have suggested that loss of function may also be a mechanism of disease (PMID: 35232796). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0600 - Variant is predicted to truncate all of the C-terminal transactivation domain (PMID: 35232796). (I) 0702 - Other protein truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two downstream truncating variants, p.(Glu415*) and p.(Glu445*), have been classified as likely pathogenic/pathogenic and have been observed in individuals with syndromic intellectual disability, one of whom is confirmed de novo and the other likely inherited the variant from a mosaic father (DECIPHER, PMID: 35232796). Other downstream truncating variants, p.(Ser390Profs*18), p.(Ser395*) and p.(Pro349alafs*68), have been classified as VUS, the latter was described as de novo in a fetus with omphalocele, abnormality of the adrenal glands and hyperechogenic kidneys (ClinVar, PMID: 36307859). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in a de novo individual with syndromic intellectual disability and has been classified as likely pathogenic (ClinVar, PMID: 35232796). (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