Submissions for variant NM_170707.4(LMNA):c.1919A>G (p.Asn640Ser)

gnomAD frequency: 0.00002  dbSNP: rs752598065

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000658526	SCV000342343	uncertain significance	not provided	2016-06-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000533234	SCV000657810	likely benign	Charcot-Marie-Tooth disease type 2	2024-10-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658526	SCV000780301	uncertain significance	not provided	2018-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000658526	SCV002000146	uncertain significance	not provided	2020-02-18	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
New York Genome Center	RCV003335301	SCV004046446	uncertain significance	Familial partial lipodystrophy, Dunnigan type	2022-10-03	criteria provided, single submitter	clinical testing	The c.1919A>G, p.(Asn640Ser) missense variant identified in the LMNA gene has not been reported in affected individuals in the literature. The variant has been reported in the ClinVar database as a Variant of Uncertain Significance (Variation ID: 288276). The c.1919A>G variant is observed in 5 alleles (~0.0008% allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1919A>G variant is located in exon 11 of this 12-exon gene, and predicted to replace a weakly conserved asparagine amino acid with serine at position 640. In silico predictions are inconclusive of deleterious effect (REVEL score = 0.333); however, there are no functional studies to support or refute these predictions. Based on available evidence the c.1919A>G, p.(Asn640Ser) missense variant identified in the LMNA gene is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV003995784	SCV004832323	uncertain significance	Primary dilated cardiomyopathy	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 640 of the LMNA protein. 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 not been reported in individuals affected with LMNA-related disorders in the literature. This variant has been identified in 2/249084 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.
PreventionGenetics, part of Exact Sciences	RCV004734939	SCV005362813	uncertain significance	LMNA-related disorder	2024-03-12	no assertion criteria provided	clinical testing	The LMNA c.1919A>G variant is predicted to result in the amino acid substitution p.Asn640Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0063% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.