ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.977C>T (p.Ser326Leu)

gnomAD frequency: 0.00002  dbSNP: rs745540806
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001176330 SCV001340268 uncertain significance Cardiomyopathy 2021-01-04 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 326 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 4/249942 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001326063 SCV001517075 uncertain significance Charcot-Marie-Tooth disease type 2 2022-12-02 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 918633). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 28416588). This variant is present in population databases (rs745540806, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 326 of the LMNA protein (p.Ser326Leu). 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.
GeneDx RCV001550193 SCV001770486 uncertain significance not provided 2020-12-15 criteria provided, single submitter clinical testing Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 918633; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31514951, 28416588)
Ambry Genetics RCV002379678 SCV002693962 uncertain significance Cardiovascular phenotype 2019-09-20 criteria provided, single submitter clinical testing The p.S326L variant (also known as c.977C>T), located in coding exon 6 of the LMNA gene, results from a C to T substitution at nucleotide position 977. The serine at codon 326 is replaced by leucine, an amino acid with dissimilar properties. This alteration was detected in an individual with DCM (Dal Ferro M et al. Heart, 2017 11;103:1704-1710). 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 RCV002483951 SCV002791294 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 2022-01-25 criteria provided, single submitter clinical testing

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