rs747952058
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PM5PP2BP4
The NM_170707.4(LMNA):c.1190G>A(p.Arg397His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R397C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1190G>A | p.Arg397His | missense_variant | 7/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.1190G>A | p.Arg397His | missense_variant | 7/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1190G>A | p.Arg397His | missense_variant | 7/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.1190G>A | p.Arg397His | missense_variant | 7/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152258Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248534Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134538
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1459570Hom.: 0 Cov.: 34 AF XY: 0.00000826 AC XY: 6AN XY: 726124
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74388
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2022 | Reported previously in a patient with HCM; however, no further clinical or segregation information was provided. Patient also had a second variant in another gene (Viswanathan et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28663758, 10939567, 29121657) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 07, 2023 | This missense variant replaces arginine with histidine at codon 397 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 hypertrophic cardiomyopathy (PMID: 29121657); this individual also carried a pathogenic variant in the MYBPC3 gene that could explain the observed phenotype. This variant has been identified in 6/279914 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. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This missense variant replaces arginine with histidine at codon 397 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 hypertrophic cardiomyopathy (PMID: 29121657); this individual also carried a pathogenic variant in the MYBPC3 gene that could explain the observed phenotype. This variant has been identified in 6/279914 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2022 | The p.R397H variant (also known as c.1190G>A), located in coding exon 7 of the LMNA gene, results from a G to A substitution at nucleotide position 1190. The arginine at codon 397 is replaced by histidine, an amino acid with highly similar properties. This variant co-occurred with a pathogenic variant in the MYBPC3 gene in an individual from a hypertrophic cardiomyopathy cohort (Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948). 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 | Nov 01, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at