Submissions for variant NM_170707.4(LMNA):c.608A>G (p.Glu203Gly)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211791	SCV000204101	pathogenic	Primary dilated cardiomyopathy	2015-08-21	criteria provided, single submitter	clinical testing	The p.Glu203Gly variant in LMNA has been reported in 1 family with DCM and condu ction system disease (Fatkin 1999), where it segregated with disease in 5 indivi duals with DCM and 4 individuals with AV block (Fatkin 1999, C. Seidman, pers co mm). One functional study suggests that this variant impacts the protein (Zhang 2008), while another had inconclusive findings (Ostlund 2001); however, these in vitro assays may not accurately represent biological function. This variant has not been identified in large population studies, but it is listed in dbSNP (rs2 8933092) without frequency information. Finally, another pathogenic variant has also been reported at this position (Glu203Lys; Jakobs 2001). In summary, this v ariant meets our criteria to be classified as pathogenic (http://pcpgm.partners. org/LMM) based upon segregation studies and absence from controls.
Invitae	RCV003581565	SCV004292910	likely pathogenic	Charcot-Marie-Tooth disease type 2	2023-06-17	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Glu203 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11561226, 18606848, 18795223, 20160190, 22464770). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 11792809, 16772334, 18606848, 25319090, 34862408). 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. ClinVar contains an entry for this variant (Variation ID: 14484). This missense change has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 10580070). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 203 of the LMNA protein (p.Glu203Gly).
OMIM	RCV000015573	SCV000035838	pathogenic	Dilated cardiomyopathy 1A	1999-12-02	no assertion criteria provided	literature only
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057428	SCV000088542	not provided	not provided		no assertion provided	not provided

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