ClinVar Miner

Submissions for variant NM_000426.4(LAMA2):c.6992+5G>A

dbSNP: rs1221715098
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657979 SCV000779750 likely pathogenic not provided 2018-05-29 criteria provided, single submitter clinical testing The c.6992+5G>A variant in the LAMA2 gene has been reported previously in the heterozygous state with a second LAMA2 variant in an individual with limb girdle muscular dystrophy, however, segregation studies to confirm phase were only performed on one parent (Harris et al., 2017). This variant is predicted to destroy the splice donor site in intron 49. Both in silico predictors and evolutionary conservation support a deleterious effect in this gene for which loss-of-function is a known mechanism for disease. The c.6992+5G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.6992+5G>A as a likely pathogenic variant.
Counsyl RCV000673048 SCV000798214 uncertain significance Merosin deficient congenital muscular dystrophy 2018-03-01 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004527719 SCV004108465 uncertain significance LAMA2-related disorder 2023-03-20 criteria provided, single submitter clinical testing The LAMA2 c.6992+5G>A variant is predicted to interfere with splicing. This variant has been reported in the heterozygous state (along with a second variant) in an individual with white matter changes (Table 1, individual 32, Harris et al. 2017. PubMed ID: 28877744). A skin biopsy for this individual demonstrated partial absence of laminin a2. In the gnomAD public population database this variant has been reported in one of ~250,000 alleles (https://gnomad.broadinstitute.org/variant/6-129781474-G-A), and is interpreted as uncertain significance and likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/546142/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp RCV005091890 SCV005834520 uncertain significance LAMA2-related muscular dystrophy 2024-04-04 criteria provided, single submitter clinical testing This sequence change falls in intron 49 of the LAMA2 gene. It does not directly change the encoded amino acid sequence of the LAMA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 28877744). ClinVar contains an entry for this variant (Variation ID: 546142). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Institute of Human Genetics, University of Wuerzburg RCV004813130 SCV005438221 likely pathogenic Muscular dystrophy, limb-girdle, autosomal recessive 23 no assertion criteria provided clinical testing

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