Submissions for variant NM_016111.4(TELO2):c.1100G>T (p.Cys367Phe)

gnomAD frequency: 0.00016  dbSNP: rs202020308

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000225284	SCV000298024	pathogenic	TELO2-related intellectual disability-neurodevelopmental disorder		criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000225284	SCV000893394	likely pathogenic	TELO2-related intellectual disability-neurodevelopmental disorder	2018-10-31	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000225284	SCV001423845	likely pathogenic	TELO2-related intellectual disability-neurodevelopmental disorder		criteria provided, single submitter	research	The TELO2 c.1100G>T likely pathogenic missense variant changes a single amino acid in the protein coding region from a cysteine to a phenylalanine. This variant has been reported to segregate with You-Hoover-Fong syndrome in two families and alters an amino acid conserved in vertebrates located within the TTI1 binding domain (PMID: 27132593).
Revvity Omics, Revvity	RCV000225284	SCV002016874	likely pathogenic	TELO2-related intellectual disability-neurodevelopmental disorder	2019-12-31	criteria provided, single submitter	clinical testing
DASA	RCV000225284	SCV002073750	likely pathogenic	TELO2-related intellectual disability-neurodevelopmental disorder	2022-02-05	criteria provided, single submitter	clinical testing	The c.1100G>T;p.(Cys367Phe) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 236225; PMID: 27132593) - PS4_moderate. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 27132593) - PS3_supporting. The variant is present at low allele frequencies population databases (rs202020308 – gnomAD 0.001708%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Cys367Phe) was detected in trans with a pathogenic variant (PMID: 27132593) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 27132593) - PP1. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854789	SCV002219342	pathogenic	not provided	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 367 of the TELO2 protein (p.Cys367Phe). This variant is present in population databases (rs202020308, gnomAD 0.06%). This missense change has been observed in individuals with You-Hoover-Fong syndrome (PMID: 27132593, 32940098). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236225). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TELO2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000225284	SCV002767160	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 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 cysteine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (43 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 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) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic, pathogenic and as a VUS by clinical laboratories in ClinVar. This variant has also been reported as compound heterozygous with other missense variants in two unrelated families with You-Hoover-Fong syndrome and an individual with moderate global developmental delay, microcephaly and other clinical features (DECIPHER, PMID: 27132593). (SP) 0903 - This variant has limited evidence for segregation with disease. It segregated with a syndromic intellectual disability disorder in a family with three affected children who were compound heterozygotes (PMID: 27132593). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional analysis using cultured fibroblasts of two unrelated patients showed a reduced amount of TELO2 protein and its partner proteins in the TTT complex (PMID: 27132593). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000225284	SCV005040547	pathogenic	TELO2-related intellectual disability-neurodevelopmental disorder	2024-03-28	criteria provided, single submitter	clinical testing	Variant summary: TELO2 c.1100G>T (p.Cys367Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 237468 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TELO2 causing TELO2-Related Intellectual Disability-Neurodevelopmental Disorder, allowing no conclusion about variant significance. c.1100G>T has been reported in the literature in multiple compound heterozygous individuals affected with TELO2-Related Intellectual Disability-Neurodevelopmental Disorder (e.g., You_2016, Del-Prado-Sanchez_2020, Albokhari_2023). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36797513, 32940098, 27132593). ClinVar contains an entry for this variant (Variation ID: 236225). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000225284	SCV000282066	pathogenic	TELO2-related intellectual disability-neurodevelopmental disorder	2019-09-10	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826054	SCV000967548	uncertain significance	not specified	2018-04-12	flagged submission	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Cys367Phe variant in TELO2 has been reported in the 2 individuals with intellectual disab ility and segregated in 2 affected family members from one family (You 2016). Al l of these individuals were compound heterozygous. This variant has also been re ported in ClinVar (Variation ID: 236225). This variant has been identified in 0. 06% (19/33748) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202020308). Although this variant has been seen in the general population, its frequency is low enough to be consiste nt with a recessive carrier frequency. Computational prediction tools and conser vation analysis suggest that the p.Cys367Phe variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. Functi onal studies provide some evidence that the p.Cys367Phe variant may impact prote in function (You 2016). However, these types of assays may not accurately repres ent biological function. In summary, while there is some suspicion for a pathoge nic role, the clinical significance of the p.Cys367Phe variant is uncertain. ACM G/AMP Criteria applied: PP1; PP3; PS3_Supporting, PM1_Supporting, PM3_Supporting
PreventionGenetics, part of Exact Sciences	RCV004757979	SCV005362675	likely pathogenic	TELO2-related disorder	2024-04-29	no assertion criteria provided	clinical testing	The TELO2 c.1100G>T variant is predicted to result in the amino acid substitution p.Cys367Phe. This variant was reported in an individual with You-Hoover-Fong syndrome (You et al 2016. PubMed ID: 27132593). This variant is reported in 0.052% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.