rs397517913
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_170707.4(LMNA):c.986G>A(p.Arg329His) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R329C) 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.986G>A | p.Arg329His | missense_variant | 6/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.986G>A | p.Arg329His | missense_variant | 6/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.986G>A | p.Arg329His | missense_variant | 6/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.986G>A | p.Arg329His | missense_variant | 6/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249996Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135436
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461610Hom.: 0 Cov.: 34 AF XY: 0.0000220 AC XY: 16AN XY: 727124
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2023 | Identified in a patient with DCM; however, detailed clinical information was not provided (Broch et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29095976, 10939567, 26468400) - |
Primary dilated cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Oct 01, 2016 | Found in patient having exome sequencing for an unrelated indication. No known history of dilated cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces arginine with histidine at codon 329 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 26468400, 29095976), one individual with unspecified cardiomyopathy (PMID 31383942), and one individual with conduction defect (PMID 31383942). This variant has been identified in 5/249996 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 06, 2012 | The Arg329His variant in LMNA has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stron g support for or against an impact to the protein. Additional information is nee ded to fully assess the clinical significance of this variant. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 24, 2023 | This missense variant replaces arginine with histidine at codon 329 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 26468400, 29095976), one individual with unspecified cardiomyopathy (PMID 31383942), and one individual with conduction defect (PMID 31383942). This variant has been identified in 5/249996 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. - |
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 329 of the LMNA protein (p.Arg329His). This variant is present in population databases (rs397517913, gnomAD 0.004%). This missense change has been observed in individual(s) with LMNA-related conditions (PMID: 26468400, 29095976, 31383942). ClinVar contains an entry for this variant (Variation ID: 48091). 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%. 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. - |
Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 12, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at