ClinVar Miner

Submissions for variant NM_000426.3(LAMA2):c.283+1G>A (rs200288072)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000444644 SCV000521017 pathogenic not provided 2016-08-11 criteria provided, single submitter clinical testing The c.283+1 G>A pathogenic variant in the LAMA2 gene has been previously reported in a patient with congenital muscular dystrophy and absent merosin staining through immunohistochemistry (Geranmayeh et al., 2010). This variant destroys the canonical splice donor site of intron 2 and cDNA and protein analysis confirmed that this variant alters splicing and results in truncated RNA and reduced protein expression. Muscle pathology from mice homozygous for the c.283+1 G>A variant showed altered morphology and structure (Xu et al., 1994). Additionally, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.283+1 G>A as a pathogenic variant.
Invitae RCV000529392 SCV000658660 pathogenic Laminin alpha 2-related dystrophy 2018-10-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 of the LAMA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs200288072, ExAC 0.01%). This variant has been reported in an individual affected with muscular dystrophy (PMID: 20207543). ClinVar contains an entry for this variant (Variation ID: 381584). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LAMA2 are known to be pathogenic (PMID: 18700894). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000665566 SCV000789711 likely pathogenic Merosin deficient congenital muscular dystrophy 2017-02-13 criteria provided, single submitter clinical testing

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