ClinVar Miner

Submissions for variant NM_025099.6(CTC1):c.775G>A (p.Val259Met)

gnomAD frequency: 0.00001  dbSNP: rs387907080
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV000023989 SCV000809082 pathogenic Cerebroretinal microangiopathy with calcifications and cysts 1 2018-04-09 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000798102 SCV000937699 pathogenic Dyskeratosis congenita 2024-03-22 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 259 of the CTC1 protein (p.Val259Met). This variant is present in population databases (rs387907080, gnomAD 0.006%). This missense change has been observed in individual(s) with Coats plus syndrome (PMID: 22267198, 29111009). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30998). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTC1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTC1 function (PMID: 24115768, 29481669). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001577148 SCV001804481 likely pathogenic not provided 2021-01-07 criteria provided, single submitter clinical testing Multiple published functional studies demonstrate a damaging effect of V259M, including abolished association with endogenous DNA polymerase alpha-primase, protein accumulation in the cytoplasm, excessive telomere loss, spontaneous chromosome breakage, severe chromosome fragmentation, reduced cellular proliferation, and poor cell survival under replication stress (Chen et al., 2013; Wang et al., 2018); This variant is associated with the following publications: (PMID: 31589614, 23220793, 22267198, 29111009, 29774655, 29481669, 24115768, 23869908, 18076099)
Genome-Nilou Lab RCV000023989 SCV002055622 likely pathogenic Cerebroretinal microangiopathy with calcifications and cysts 1 2021-07-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000023989 SCV002790998 likely pathogenic Cerebroretinal microangiopathy with calcifications and cysts 1 2021-08-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV000023989 SCV003835278 pathogenic Cerebroretinal microangiopathy with calcifications and cysts 1 2022-06-13 criteria provided, single submitter clinical testing
OMIM RCV000023989 SCV000045280 pathogenic Cerebroretinal microangiopathy with calcifications and cysts 1 2012-01-22 no assertion criteria provided literature only

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