ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1824C>T (p.Gly608=) (rs58596362)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150957 SCV000198623 pathogenic Primary dilated cardiomyopathy; Hutchinson-Gilford syndrome 2018-02-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000057364 SCV000225440 pathogenic not provided 2013-07-01 criteria provided, single submitter clinical testing
GeneDx RCV000057364 SCV000293400 pathogenic not provided 2016-02-04 criteria provided, single submitter clinical testing The de novo c.1824C>T variant in the LMNA gene is the cause of classic Hutchinson-Gilford progeria syndrome in approximately 90% of cases (Rodriguez et al., 2009; Lopez-Mejia et al., 2011; Chu et al., 2015; Ericksson et al., 2003). This variant creates a cryptic splice donor site within exon 11 and causes abnormal gene splicing. The c.1824C>T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies of c.1824C>T indicate that it causes increased expression of abnormal truncated protein during in vitro cell aging (Rodriguez et al., 2009; Lopez-Mejia et al., 2011). The c.1824C>T variant has been classified as a pathogenic variant by other clinical laboratories in ClinVar (Landrum et al., 2014). We interpret c.1824C>T as a pathogenic variant
Genetic Services Laboratory,University of Chicago RCV000015593 SCV000595639 pathogenic Hutchinson-Gilford syndrome 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000806737 SCV000946752 pathogenic Charcot-Marie-Tooth disease, type 2 2019-11-13 criteria provided, single submitter clinical testing This sequence change affects codon 608 of the LMNA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LMNA protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals affected with Hutchinson-Gilford progeria syndrome (HGPS) (PMID: 12768443, 22148005, 23141186, 22685055, 15793835, Invitae) including multiple de novo observations (PMID: 12714972, 25946677, 17459035, 22611635). This variant is the cause of approximately 90% of HGPS cases (PMID: 19172989). This variant is also known as c.2036C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 14500). This variant has been reported to increase expression of an abnormal truncated protein called progerin in vitro (PMID: 19172989, 21875900), disrupt stem cell functions involved in tissue repair (PMID: 25567453), and result in dysmorphic nuclei in patient fibroblasts (PMID: 12714972, 15982412). This variant recapitulates the HGPS phenotype in mouse models (PMID: 22893709, 24305605, 21875900, 23969228). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 21875900, 15982412, 12714972, 28679633). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015593 SCV000035858 pathogenic Hutchinson-Gilford syndrome 2009-07-01 no assertion criteria provided literature only
OMIM RCV000015594 SCV000035859 pathogenic Lethal tight skin contracture syndrome 2009-07-01 no assertion criteria provided literature only
Epithelial Biology; Institute of Medical Biology, Singapore RCV000057364 SCV000088477 not provided not provided no assertion provided not provided
GeneReviews RCV000015593 SCV000196620 pathogenic Hutchinson-Gilford syndrome 2015-01-08 no assertion criteria provided literature only

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