ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.448A>G (p.Thr150Ala) (rs58917027)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208276 SCV000264007 likely pathogenic Primary dilated cardiomyopathy 2014-12-11 criteria provided, single submitter clinical testing
Invitae RCV000536399 SCV000657813 uncertain significance Charcot-Marie-Tooth disease, type 2 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 150 of the LMNA protein (p.Thr150Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LMNA-related disease. ClinVar contains an entry for this variant (Variation ID: 222692). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Thr150 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 10908904, 20848652, 24503780), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000611547 SCV000731631 uncertain significance not specified 2017-05-02 criteria provided, single submitter clinical testing The p.Thr150Ala variant in LMNA has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis suggest that the p.Thr150Ala variant may not impact the protein, though this information is not predictive enough to rule out patho genicity. This variant has been reported in ClinVar (Variation ID: 222692). Of n ote, a change that the same codon (p.Thr150Pro) has been classified as likely pa thogenic (LMM data), suggesting that changes at this position may not be tolerat ed. In summary, the clinical significance of the p.Thr150Ala variant is uncertai n.

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