rs373671419
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2PP2BP4_ModerateBP6
The NM_170707.4(LMNA):c.1657G>A(p.Asp553Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000296 in 1,555,816 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. D553H) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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LMNA | NM_170707.4 | c.1657G>A | p.Asp553Asn | missense_variant | Exon 10 of 12 | ENST00000368300.9 | NP_733821.1 | |
LMNA | NM_005572.4 | c.1657G>A | p.Asp553Asn | missense_variant | Exon 10 of 10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1657G>A | p.Asp553Asn | missense_variant | Exon 10 of 12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
LMNA | ENST00000677389.1 | c.1657G>A | p.Asp553Asn | missense_variant | Exon 10 of 10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000984 AC: 16AN: 162670Hom.: 0 AF XY: 0.000128 AC XY: 11AN XY: 85804
GnomAD4 exome AF: 0.0000164 AC: 23AN: 1403638Hom.: 0 Cov.: 31 AF XY: 0.0000245 AC XY: 17AN XY: 692560
GnomAD4 genome AF: 0.000151 AC: 23AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:3
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In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published in association with an LMNA-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 10939567, 28679633, 27884249) -
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not specified Benign:2
The p.Asp553Asn variant in LMNA is classified as likely benign because it has been identified in 0.06% (15/24926) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Additionally, 2 mammals (rat and mouse) have an asparagine (Asn) at this position despite relatively nearby amino acid conservation. In addition, most computational tools do not suggest a high likelihood of impact to the protein. ACMG/AMP Criteria applied: BS1_supporting, BP4. -
Variant summary: LMNA c.1657G>A (p.Asp553Asn) results in a conservative amino acid change in 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 3e-05 in 1549110 control chromosomes, predominantly at a frequency of 0.00074 within the Latino subpopulation in the gnomAD database (v4.1 dataset). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in LMNA causing Cardiomyopathy phenotype (0.00025). c.1657G>A has been reported in the literature in individuals affected with cardiomyopathy and (suspected) muscular dystrophy (e.g. Kumar_2016, Nallamilli_2018), however no supportive evidence for causality was provided. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27884249, 30564623). ClinVar contains an entry for this variant (Variation ID: 286258). Based on the evidence outlined above, the variant was classified as likely benign. -
Charcot-Marie-Tooth disease Uncertain:1
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Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
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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
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Cardiovascular phenotype Uncertain:1
The p.D553N variant (also known as c.1657G>A), located in coding exon 10 of the LMNA gene, results from a G to A substitution at nucleotide position 1657. The aspartic acid at codon 553 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in a ventricular tachycardia cohort (Kumar S et al. Circ Arrhythm Electrophysiol, 2016 08;9:; Kumar S et al. J Am Coll Cardiol, 2016 Nov;68:2299-2307). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Cardiomyopathy Benign:1
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Charcot-Marie-Tooth disease type 2 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at