Submissions for variant NM_170707.4(LMNA):c.1873_1874delinsCC (p.Ser625Pro)

dbSNP: rs1553266553

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000622044	SCV000736318	uncertain significance	Cardiovascular phenotype	2024-04-19	criteria provided, single submitter	clinical testing	The c.1873_1874delAGinsCC variant (also known as p.S625P), located in coding exon 11 of the LMNA gene, results from an in-frame deletion of AG and insertion of CC at nucleotide positions 1873 to 1874. This results in the substitution of the serine residue for a proline residue at codon 625, an amino acid with similar properties. This variant co-occurred with a variant in another cardiac related gene in a proband with hypertrophic cardiomyopathy from a sudden death cohort (Quenin P. Circ Arrhythm Electrophysiol. 2017 Sep;10(9)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on data from gnomAD, this allele has an overall frequency of 0.0036% (10/280002) total alleles studied. The highest observed frequency was 0.033% (10/24582) of African alleles. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822504	SCV000963311	uncertain significance	Charcot-Marie-Tooth disease type 2	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 625 of the LMNA protein (p.Ser625Pro). This variant is present in population databases (no rsID available, gnomAD 0.4%). 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: 518817). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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.
Color Diagnostics, LLC DBA Color Health	RCV001185275	SCV001351450	uncertain significance	Cardiomyopathy	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with proline at codon 625 of the LMNA protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden cardiac death (PMID: 28912206). A different DNA substitution with the same protein effect c.1875C>A (p.Ser625Pro) has been reported in an individual affected with dilated cardiomyopathy (PMID: 29892087). This variant has not been identified 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.
Fulgent Genetics, Fulgent Genetics	RCV002498997	SCV002777156	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	2022-01-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004735679	SCV005361183	uncertain significance	LMNA-related disorder	2024-06-28	no assertion criteria provided	clinical testing	The LMNA c.1873_1874delinsCC variant is predicted to result in an in-frame deletion and insertion. This variant has been reported as a variant of uncertain significance in an individual with hypertrophic cardiomyopathy and sudden cardiac death (described as c.1873A>C and c.1874G>C in Table 2, Quenin et al. 2017. PubMed ID: 28912206). This variant can be documented as two individual variants in a large population database, each with a subpopulation frequency of 0.0326% (c.1873A>C and c.1874G>C; https://gnomad.broadinstitute.org/variant/1-156108453-AG-CC?dataset=gnomad_r2_1). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.