ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.143G>C (p.Arg48Pro)

dbSNP: rs1572332235
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000800232 SCV000939932 pathogenic Charcot-Marie-Tooth disease type 2 2024-02-23 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 48 of the LMNA protein (p.Arg48Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital muscular dystrophy (PMID: 26098624). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 646027). 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 LMNA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LMNA function (PMID: 26098624). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV003235401 SCV003933242 pathogenic not provided 2022-12-12 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as this variant results in abnormal protein aggregation (Tan et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10939567, 26098624, 32571898, 34240052)

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