NM_000426.4:c.725G>A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000426.4(LAMA2):c.725G>A(p.Arg242His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,612,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000426.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 151792Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000108 AC: 27AN: 250822Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135554
GnomAD4 exome AF: 0.0000527 AC: 77AN: 1460416Hom.: 0 Cov.: 31 AF XY: 0.0000592 AC XY: 43AN XY: 726574
GnomAD4 genome AF: 0.000125 AC: 19AN: 151910Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74260
ClinVar
Submissions by phenotype
not specified Uncertain:1
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LAMA2-related muscular dystrophy Uncertain:1
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 242 of the LAMA2 protein (p.Arg242His). This variant is present in population databases (rs373570586, gnomAD 0.06%). This missense change has been observed in individual(s) with congenital Muscular Dystrophy (PMID: 32266982). ClinVar contains an entry for this variant (Variation ID: 218454). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LAMA2 protein function. 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. -
not provided Uncertain:1
Reported previously with another LAMA2 variant (phase unknown) in a patient with congenital myopathy (Hayes et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32266982, 32028919) -
Merosin deficient congenital muscular dystrophy;C4748327:Muscular dystrophy, limb-girdle, autosomal recessive 23 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at