Submissions for variant NM_170707.4(LMNA):c.1825G>A (p.Gly609Arg)

gnomAD frequency: 0.00001  dbSNP: rs397517898

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041335	SCV000065028	uncertain significance	not specified	2010-09-21	criteria provided, single submitter	clinical testing	The Gly609Arg variant has not been reported in the literature nor identified in any other families tested by our laboratory. This variant affects only one of tw o RNAs generated by the LMNA gene. Glycine (Gly) at position 609 is not 100% con served across different species (lizard carries a serine and frog carries a thre onine), reducing the likelihood that the change is pathogenic. On the other hand segregation of the Gly609Arg variant in this family is so far consistent with a disease causing role and autosomal dominant inheritance.
Color Diagnostics, LLC DBA Color Health	RCV001804765	SCV002052165	uncertain significance	Cardiomyopathy	2021-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 609 of the lamin A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant represents a single nucleotide substitution in the 3' untranslated region of the lamin C transcript (ENST00000361308: c.*850G>A). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/246826 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001852840	SCV002193188	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 609 of the LMNA protein (p.Gly609Arg). This variant is present in population databases (rs397517898, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 48053). 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%. 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.
Fulgent Genetics, Fulgent Genetics	RCV002483028	SCV002784624	uncertain significance	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2	2021-10-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162352	SCV003900580	uncertain significance	Cardiovascular phenotype	2022-11-14	criteria provided, single submitter	clinical testing	The p.G609R variant (also known as c.1825G>A), located in coding exon 11 of the LMNA gene, results from a G to A substitution at nucleotide position 1825. The glycine at codon 609 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003320549	SCV004025580	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been published in association with LMNA-related disease to our knowledge; This variant is associated with the following publications: (PMID: 28679633, 30402260, 10939567)
PreventionGenetics, part of Exact Sciences	RCV003398610	SCV004103817	uncertain significance	LMNA-related condition	2023-09-22	criteria provided, single submitter	clinical testing	The LMNA c.1825G>A variant is predicted to result in the amino acid substitution p.Gly609Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-156108405-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.