chr1-156138701-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2PP2BP4_StrongBP6
The NM_170707.4(LMNA):c.1912G>A(p.Gly638Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000104 in 1,613,114 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). Synonymous variant affecting the same amino acid position (i.e. G638G) has been classified as Likely benign.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1912G>A | p.Gly638Arg | missense_variant | 11/12 | ENST00000368300.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1912G>A | p.Gly638Arg | missense_variant | 11/12 | 1 | NM_170707.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000560 AC: 85AN: 151820Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000137 AC: 34AN: 248930Hom.: 0 AF XY: 0.0000888 AC XY: 12AN XY: 135118
GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461294Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34AN XY: 726980
GnomAD4 genome ? AF: 0.000560 AC: 85AN: 151820Hom.: 0 Cov.: 32 AF XY: 0.000593 AC XY: 44AN XY: 74146
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2023 | Reported in association with cardiolaminopathy and DCM (Narula et al., 2012; van Rijsingen et al., 2013; Pugh et al., 2014); however, segregation data were not provided, and Pugh et al. (2014) classified this variant as likely benign due to the minor allele frequency exceeding their set thresholds; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 23062543, 28663758, 23299917, 25617006, 32616434, 23183350, 35898701, 30564623, 10939567) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 10, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 14, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 20, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 30, 2022 | The LMNA c.1912G>A; p.Gly638Arg variant (rs144851946) is reported in the literature in several cohorts of individuals with cardiac dysfunction (Narula 2012, van Rijsingen 2013), but to our knowledge this variant has not been described in association with Charcot-Marie-Tooth disease or related hereditary neuropathies. This variant is reported in ClinVar (Variation ID: 48056) and is found in the African population with an overall allele frequency of 0.21% (51/24610 alleles) in the Genome Aggregation Database. The glycine at codon 638 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.477). However, due to limited information, the clinical significance of the p.Gly638Arg variant is uncertain at this time. References: Narula et al. Quantitative expression of the mutated lamin A/C gene in patients with cardiolaminopathy. J Am Coll Cardiol. 2012 Nov 6;60(19):1916-20. PMID: 23062543. van Rijsingen et al. Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers. Eur J Heart Fail. 2013 Apr;15(4):376-84. PMID: 23183350. - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 14, 2012 | Gly638Arg in exon 11 of LMNA: This variant is not expected to have clinical sign ificance because it has been identified in 0.3% (12/4406) African American chrom osomes from a broad population by the NHLBI Exome Sequencing Project (http://evs .gs.washington.edu/EVS; dbSNP rs144851946). Gly638Arg in exon 11 of LMNA (rs144 851946; allele frequency = 0.3%, 12/4406) ** - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 11, 2023 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 02, 2018 | - - |
Charcot-Marie-Tooth disease type 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
LMNA-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 21, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at