Submissions for variant NM_170707.4(LMNA):c.1960C>T (p.Arg654Ter)

gnomAD frequency: 0.00002  dbSNP: rs267607544

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035240	SCV001198560	uncertain significance	Charcot-Marie-Tooth disease type 2	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg654*) in the LMNA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the LMNA protein. This variant is present in population databases (rs267607544, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Emery-Dreifuss muscular dystrophy and an individual affected with dilated cardiomyopathy (PMID: 29693488, 30012837). ClinVar contains an entry for this variant (Variation ID: 66877). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects LMNA function (PMID: 20160190). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000057375	SCV002501416	uncertain significance	not provided	2021-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415511	SCV002720118	uncertain significance	Cardiovascular phenotype	2021-07-07	criteria provided, single submitter	clinical testing	The p.R654* variant (also known as c.1960C>T), located in coding exon 11 of the LMNA gene, results from a C to T substitution at nucleotide position 1960. This changes the amino acid from an arginine to a stop codon within coding exon 11. This alteration occurs at the 3' terminus of theLMNA gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 11 amino acids of the protein. The exact functional effect of this alteration is unknown. This variant was reported in a family with dilated cardiomyopathy (DCM) with segregation in three affected family members, and absence in three other affected family members; an additional cardiac variant in PLN was also detected in the proband and the three affected family members without the LMNA variant (Parks SB et al. Am. Heart J., 2008 Jul;156:161-9; Cowan JR et al. Circ Genom Precis Med, 2018 Jul;11:e002038). This alteration was also detected in an individual with Hutchinson-Gilford Progeria syndrome, who was homozygous for a ZMPSTE24 loss of function variant, as well as in his unaffected mother and brother (Denecke J et al. Hum. Mutat., 2006 Jun;27:524-31). In addition, the variant was reported in an individual with Emery Dreifuss muscular dystrophy type 2 with symptoms of axonal neuropathy (Denecke J et al. Hum. Mutat., 2006 Jun;27:524-31; Bernasconi P et al. Nucleus, 2018 Jan;9:292-304). Functional studies showed formation of protein aggregates, but the functional impact of this finding has not been determined (Cowan J et al. Circ Cardiovasc Genet, 2010 Feb;3:6-14). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002483090	SCV002782960	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	2021-10-17	criteria provided, single submitter	clinical testing
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057375	SCV000088488	not provided	not provided		no assertion provided	not provided
University of Washington Center for Mendelian Genomics, University of Washington	RCV001257939	SCV001434749	uncertain significance	Primary dilated cardiomyopathy		no assertion criteria provided	research