rs56851164
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_170707.4(LMNA):c.976T>A(p.Ser326Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S326L) has been classified as Uncertain significance.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.976T>A | p.Ser326Thr | missense_variant | 6/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.976T>A | p.Ser326Thr | missense_variant | 6/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.976T>A | p.Ser326Thr | missense_variant | 6/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.976T>A | p.Ser326Thr | missense_variant | 6/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000560 AC: 14AN: 249958Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135434
GnomAD4 exome AF: 0.0000855 AC: 125AN: 1461604Hom.: 0 Cov.: 34 AF XY: 0.0000811 AC XY: 59AN XY: 727126
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74304
ClinVar
Submissions by phenotype
not provided Uncertain:3Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 16, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 01, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22071332, 23142632, 16585054, 27532257, 16407522, 20627339, 28663758, 9536090, 22224630, 28518168, 31019283, 29095976, 29237690, 28679633, 24846508, 10939567, 34862408, 34240052, 36975868, 33673806, 31476771, 24503780) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 08, 2015 | - - |
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 31, 2023 | Variant summary: LMNA c.976T>A (p.Ser326Thr) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 249958 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LMNA causing Dilated Cardiomyopathy (5.6e-05 vs 0.0001), allowing no conclusion about variant significance. c.976T>A has been reported in the literature in individuals affected with Cardiomyopathy or muscle laminopathy without strong evidence of causality (e.g. Muntoni_2006, Pugh_2014, Walsh_2017, Ben Yaou_2021, Hathaway_2021, Park_2020). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. At least one publication reports experimental evidence evaluating an impact on protein function, finding no effect of the variant on laminim A aggregation (Anderson_2021). The following publications have been ascertained in the context of this evaluation (PMID: 16585054, 23142632, 24503780, 27532257, 31019283, 34862408, 34240052, 33673806, 31383942, 25274841, 22071332). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7), likely pathogenic (n=1) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 03, 2018 | The LMNA c.976T>A; p.Ser326Thr variant (rs56851164), is reported in the literature in individuals affected with dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy (Hasselberg 2018, Muntoni 2006, Pugh 2014), and is reported in ClinVar (Variation ID: 48097). In a family with X-linked Emery-Dreifuss muscular dystrophy segregating with a STA p.Tyr105Ter variant, a presumed de novo LMNA c.976T>A; p.Ser326Thr variant was identified in one affected individual presenting with much more severe clinical symptoms than two other affected family members. This variant occurs in the functionally important coil 2B domain that mediates lamin A/C oligomerization; however, molecular dynamics modeling of the LMNA c.976T>A; p.Ser326Thr variant suggested no effect on protein dimerization, although the authors concede other mechanisms could still account for pathogenicity (Gangemi 2013). This variant is found in the non-Finnish European population with an overall allele frequency of 0.012% (15/126146 alleles) in the Genome Aggregation Database, and a recent study classified this variant as likely benign due to its population frequency above a maximum allele frequency threshold (MAF < 0.01%) expected for pathogenic variants (Walsh 2017). The serine at codon 326 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to conflicting information, the clinical significance of the LMNA c.976T>A; p.Ser326Thr variant is uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 19, 2018 | Variant classified as Uncertain Significance - Favor Pathogenic. The Ser326Thr v ariant in LMNA has been reported in 7 individuals with a range of cardio-muscula r manifestations, including 5 individuals with DCM and/or conduction system dise ase (CSD), 1 with late-onset scapular myopathy and CSD, and 1 with early-onset X -linked EDMD that also carried a pathogenic EMD variant (Muntoni 2006, Meune 200 6, Ito 2017, Hasselberg 2018). This variant has also been identified in 15/12614 6 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs56851164). In vitro functional studies provide some evidence that the p.Ser326Thr variant may not impact protein function (Gangemi 2013). However, these types of assays may not accurately represent biological fu nction. In addition, serine (Ser) at position 326 is not conserved in evolution with 5 species carrying a threonine (Thr), suggesting that this change may be to lerated. In summary, while there is some suspicion for a pathogenic role, the cl inical significance of the p.Ser326Thr variant is uncertain due to conflicting e vidence. ACMG/AMP Criteria applied: PM6; PS4; BP4, BS3_Supporting. - |
Dilated cardiomyopathy 1A Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Feb 02, 2024 | ACMG Criteria: PM2_P, PP5; Variant was found in heterozygous state - |
Uncertain significance, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, flagged submission | clinical testing | Blueprint Genetics | Sep 14, 2015 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 15, 2022 | This missense variant replaces serine with threonine 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 been reported in an individual affected with unspecified LMNA-associated muscular phenotype (PMID: 16407522), and in three unrelated individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257, 29095976). This variant has been reported as de novo in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 16585054). This and two other affected individuals from this family carried a pathogenic p.Tyr105* variant in the same gene. This variant has been reported in three additional individuals affected with Emery-Dreifuss muscular dystrophy, one individual affected with late-onset scapular myopathy and two individuals affected with dilated cardiomyopathy (PMID: 16585054). This variant has also been identified in 15/281330 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant of unknown impact on function that has been observed in affected individuals as well as in the general population. 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. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces serine with threonine 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 been reported in an individual affected with unspecified LMNA-associated muscular phenotype (PMID: 16407522), and in three unrelated individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257, 29095976). This variant has been reported as de novo in an individual affected with Emery-Dreifuss muscular dystrophy (PMID: 16585054). This and two other affected individuals from this family carried a pathogenic p.Tyr105* variant in the same gene. This variant has been reported in three additional individuals affected with Emery-Dreifuss muscular dystrophy, one individual affected with late-onset scapular myopathy and two individuals affected with dilated cardiomyopathy (PMID: 16585054). This variant has also been identified in 15/281330 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this is a variant of unknown impact on function that has been observed in affected individuals as well as in the general population. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2022 | The p.S326T variant (also known as c.976T>A), located in coding exon 6 of the LMNA gene, results from a T to A substitution at nucleotide position 976. The serine at codon 326 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in individuals reported to have conduction system disease and various myopathies, including dilated cardiomyopathy, late-onset scapular myopathy, and Emery-Dreifuss muscular dystrophy; however, some patients had variants in other genes and, in some cases, clinical detail and/or gene analysis were limited (Muntoni F et al. Brain. 2006;129:1260-8; Hasselberg NE et al. Eur Heart J. 2018 03;39(10):853-860Pugh TJ et al. Genet. Med. 2014;16:601-8; Peretto G et al. Ann Intern Med. 2019 10;171(7):458-463). This variant has also been detected in a hypertrophic cardiomyopathy genetic testing cohort and in cohorts not selected for the presence of LMNA-related disease, but clinical details were limited (Florwick A et al. Front Genet. 2017;8:79; Thauvin-Robinet C et al. Eur J Hum Genet. 2019 08;27(8):1197-1214; Hathaway J et al. BMC Cardiovasc Disord. 2021 03;21(1):126). 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. - |
Charcot-Marie-Tooth disease type 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at