ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.884C>T (p.Ser295Leu)

gnomAD frequency: 0.00002  dbSNP: rs769210828
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617558 SCV000736768 uncertain significance Cardiovascular phenotype 2017-03-02 criteria provided, single submitter clinical testing The p.S295L variant (also known as c.884C>T), located in coding exon 5 of the LMNA gene, results from a C to T substitution at nucleotide position 884. The serine at codon 295 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). Another alteration affecting this amino acid (p.S295P, c.883T>C) has been reported in a single individual with muscular dystrophy and cardiomyopathy with conduction disease (Scharner J et al. Hum. Mutat., 2011 Feb;32:152-67). That alteration has been shown to produce abnormal Lamin A localization, nuclear shape, and Lamin B1/emerin distribution compared to wild-type Lamin A (Scharner J et al. Gene Ther., 2015 Jun;22:503-15). 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.
Color Diagnostics, LLC DBA Color Health RCV000772649 SCV000905908 uncertain significance Cardiomyopathy 2023-07-06 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 295 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 been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666), in an individual affected with unspecified cardiomyopathy (PMID: 35581137), and in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 7/281984 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 RCV001041442 SCV001205062 uncertain significance Charcot-Marie-Tooth disease type 2 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 295 of the LMNA protein (p.Ser295Leu). This variant is present in population databases (rs769210828, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20848652, 34621001; Invitae). ClinVar contains an entry for this variant (Variation ID: 518983). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LMNA function (PMID: 34862408). 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.
Loeys Lab, Universiteit Antwerpen RCV001375642 SCV001572567 uncertain significance Primary dilated cardiomyopathy 2021-02-26 criteria provided, single submitter clinical testing This sequence change results in a missense variant in the LMNA gene (p.(Ser295Leu)) (PP2; based on GnomAd constraint matrix). The variant is described in LVOD as variant of unknown significance (LMNA_000421). This variant is present in GnomAD with a prevalence of 7/276586.This variant has been described in literature in an individual with HCM (PMID: 25351510) but was also seen in a control-population (PMID: 28663758) .The variant affects a weakly conserved nucleotide and a moderately conserved amino acid. Prediction programs classify the variant as benign (Align GVGD: C0; Polyphen-2-HumDiv: benign ; Polyphen-2-HumVar: benign; SIFT: tolerated; MutationTaster: no result) (BP4). It is located in the intermediate filament rod domain of the LMNA protein. Functional assays have not been performed for this variant. We identified this variant in a 2 unrelated patients with DCM and a third unrelated patient presenting with refractory Ventricular tachycardia in absence of structural cardiac abnormalities. No data on segregation were available. In conclusion this variant was classified as variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met: BS4, PP2).
Revvity Omics, Revvity Omics RCV001700259 SCV003814721 uncertain significance not provided 2022-01-25 criteria provided, single submitter clinical testing
GeneDx RCV001700259 SCV003853056 uncertain significance not provided 2023-03-28 criteria provided, single submitter clinical testing Reported previously as a variant of uncertain significance in a parent whose child had a diagnosis of heterotaxy; however, no further clinical information was provided on the parent and it was unclear if the child also harbored the variant (Chetruengchai and Shotelersuk, 2022); Reported previously in an individual diagnosed with HCM; however, further clinical, family history, and segregation details were unavailable (Lopes et al., 2015); Reported previously as a variant of uncertain significance in a patient with non-ischemic cardiomyopathy and previous heart transplantation; however, further clinical and segregation information was provided (Boen et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28663758, 10939567, 34621001, 35581137, 25351510)
Clinical Genetics, Academic Medical Center RCV001700259 SCV001917681 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001700259 SCV001957371 uncertain significance not provided no assertion criteria provided clinical testing

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