Submissions for variant NM_170707.4(LMNA):c.1601C>G (p.Thr534Ser)

gnomAD frequency: 0.00001  dbSNP: rs144740174

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001526170	SCV001736467	uncertain significance	Cardiomyopathy	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 534 of the lamin A/C proteins. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital muscular dystrophy (PMID: 28688748). This variant has been identified in 1/198866 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	RCV001873693	SCV002314465	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-06-06	criteria provided, single submitter	clinical testing	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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LMNA protein function. ClinVar contains an entry for this variant (Variation ID: 1172352). This missense change has been observed in individual(s) with clinical features of congenital muscular dystrophy (PMID: 28688748). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 534 of the LMNA protein (p.Thr534Ser).
Ambry Genetics	RCV002405217	SCV002708663	uncertain significance	Cardiovascular phenotype	2023-10-17	criteria provided, single submitter	clinical testing	The p.T534S variant (also known as c.1601C>G), located in coding exon 9 of the LMNA gene, results from a C to G substitution at nucleotide position 1601. The threonine at codon 534 is replaced by serine, an amino acid with similar properties. This alteration has been reported in the heterozygous state in a proband with congenital muscular dystrophy phenotype (Sframeli M et al. Neuromuscul Disord, 2017 Sep;27:793-803). This amino acid position is not 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.
Fulgent Genetics, Fulgent Genetics	RCV002495848	SCV002791420	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	2021-07-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003136095	SCV003814693	uncertain significance	not provided	2019-05-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004008896	SCV004818594	uncertain significance	Primary dilated cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 534 of the lamin A/C proteins. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital muscular dystrophy (PMID: 28688748). This variant has been identified in 1/198866 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.