Submissions for variant NM_031407.7(HUWE1):c.12650G>C (p.Gly4217Ala)

dbSNP: rs1556910261

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498486	SCV000589742	likely pathogenic	not provided	2016-02-29	criteria provided, single submitter	clinical testing	The G4217A variant in the HUWE1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G4217A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G4217A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The G4217A variant is a strong candidate for a pathogenic variant
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004594066	SCV005085953	likely pathogenic	Intellectual disability, X-linked syndromic, Turner type	2024-09-20	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 and gain of function are known mechanisms of disease in this gene and are associated with intellectual developmental disorder, X-linked syndromic, Turner type (MIM#309590, PMID:29180823). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. However, this variant is located close to the intron-exon junction and may have a splice effect. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Additionally, splice in silico predictors support an effect on splicing. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. There is one likely pathogenic report in ClinVar by GeneDx, where the variant was found to be de novo in an individual with intellectual disability, short stature, relative macrocephaly and dysmorphic features (ClinVar). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign