Submissions for variant NM_000426.4(LAMA2):c.8245-2A>G

dbSNP: rs914395925

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414051	SCV000491204	pathogenic	not provided	2016-11-15	criteria provided, single submitter	clinical testing	The c.8245-2 A>G pathogenic variant was previously reported in a patient with congenital muscular dystrophy type 1A, who harbored an additional LAMA2 variant (Beytia et al., 2014). This variant destroys the canonical splice acceptor site for intron 58. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subjected to nonsense-mediated mRNA decay, or to abnormal protein product if the message is used for protein translation. The c.8245-2 A>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations
Illumina Laboratory Services, Illumina	RCV000779488	SCV000916121	likely pathogenic	Congenital muscular dystrophy due to partial LAMA2 deficiency	2018-12-07	criteria provided, single submitter	clinical testing	The LAMA2 c.8245-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in two individuals affected with congenital muscular dystrophy, both in a compound heterozygous state with a deletion or stop-gained variant (Beytia et al. 2014; Oliveira et al. 2018). This variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the evidence and the potential impact of splice acceptor variants, the c.8245-2A>G variant is classified as likely pathogenic for LAMA2-related congenital muscular dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV003463817	SCV004190529	pathogenic	Merosin deficient congenital muscular dystrophy	2023-03-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003574768	SCV004273937	pathogenic	LAMA2-related muscular dystrophy	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 58 of the LAMA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LAMA2 are known to be pathogenic (PMID: 18700894, 32904964). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with LAMA2-related muscular dystrophy (PMID: 24225367, 30055037). ClinVar contains an entry for this variant (Variation ID: 372750). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.