Submissions for variant NM_016111.4(TELO2):c.392G>A (p.Gly131Asp)

gnomAD frequency: 0.00006  dbSNP: rs187225056

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486946	SCV000566657	likely pathogenic	not provided	2022-11-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001249831	SCV001423844	uncertain significance	TELO2-related intellectual disability-neurodevelopmental disorder		criteria provided, single submitter	research	The TELO2 c.392G>A p.G131D missense variant of uncertain significance is predicted to change a single amino acid from glycine to aspartic acid.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001249831	SCV002767161	likely pathogenic	TELO2-related intellectual disability-neurodevelopmental disorder	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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with You-Hoover-Fong syndrome (MIM#616954). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by a clinical laboratory in ClinVar, and has also been classified as likely pathogenic in two individuals with TELO2-related disorders, where the variant was observed in trans with other likely pathogenic TELO2 variants (DECIPHER). This variant has also been classified as a VUS in an individual with moderate intellectual disability where it was seen in trans with another TELO2 VUS (DECIPHER). (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) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Invitae	RCV000486946	SCV003261547	uncertain significance	not provided	2022-04-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 131 of the TELO2 protein (p.Gly131Asp). This variant is present in population databases (rs187225056, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TELO2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419090). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.