Submissions for variant NM_198253.3(TERT):c.430G>A (p.Val144Met)

dbSNP: rs199422291

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256024	SCV000322340	pathogenic	not provided	2016-03-18	criteria provided, single submitter	clinical testing	The V144M variant in the TERT gene has been published previously in association with familial pulmonary fibrosis and lung disease (Diaz et al., 2010; Tsakiri et al., 2007). The variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position within the GQ motif of the TEN domain that is not conserved. However, functional studies have shown that while V144M does not affect activity of the TERT protein, it prevents localization of the protein to telomeres, resulting in telomere shortening (Zhong et al., 2012).
Invitae	RCV002513303	SCV001214287	uncertain significance	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2022-06-12	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change affects TERT function (PMID: 22364217, 22863003, 25271372). 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 TERT protein function. ClinVar contains an entry for this variant (Variation ID: 39124). This missense change has been observed in individual(s) with idiopathic pulmonary fibrosis (PMID: 17460043, 20502709). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 144 of the TERT protein (p.Val144Met).
Mayo Clinic Laboratories, Mayo Clinic	RCV000256024	SCV002103210	pathogenic	not provided	2022-06-02	criteria provided, single submitter	clinical testing	PP1, PM2, PS3, PS4
GeneReviews	RCV000032397	SCV000056053	not provided	Interstitial lung disease 2		no assertion provided	literature only
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center	RCV002509178	SCV002547419	likely risk allele	Pulmonary fibrosis	2022-06-09	no assertion criteria provided	research	Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted