rs773209126
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000426.4(LAMA2):c.1303C>T(p.Arg435Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,595,748 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000426.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMA2 | NM_000426.4 | c.1303C>T | p.Arg435Ter | stop_gained | 9/65 | ENST00000421865.3 | |
LAMA2 | NM_001079823.2 | c.1303C>T | p.Arg435Ter | stop_gained | 9/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMA2 | ENST00000421865.3 | c.1303C>T | p.Arg435Ter | stop_gained | 9/65 | 5 | NM_000426.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152090Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249702Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134836
GnomAD4 exome AF: 0.0000222 AC: 32AN: 1443658Hom.: 0 Cov.: 27 AF XY: 0.0000209 AC XY: 15AN XY: 719126
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74288
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Dec 27, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 27, 2023 | Reported previously in multiple individuals with congenital muscular dystrophy with contractures and scoliosis who also possessed a second LAMA2 variant (Geranmayeh et al., 2010; Liang et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 20207543, 28182637, 30055037, 32444167, 33558818, 31847883, 32904964) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 10, 2015 | - - |
Merosin deficient congenital muscular dystrophy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 24, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
LAMA2-related muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change creates a premature translational stop signal (p.Arg435*) in the LAMA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA2 are known to be pathogenic (PMID: 18700894, 32904964). This variant is present in population databases (rs773209126, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with congenital muscular dystrophy (PMID: 20207543, 24611677, 28182637). ClinVar contains an entry for this variant (Variation ID: 235805). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at