Submissions for variant NM_000426.4(LAMA2):c.5325dup (p.Leu1776fs)

dbSNP: rs768458445

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666437	SCV000790729	likely pathogenic	Merosin deficient congenital muscular dystrophy	2017-04-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055589	SCV001219989	pathogenic	LAMA2-related muscular dystrophy	2024-04-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1776Thrfs*3) 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 (rs768458445, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with muscular dystrophy (PMID: 20207543). ClinVar contains an entry for this variant (Variation ID: 551387). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001055589	SCV003934506	pathogenic	LAMA2-related muscular dystrophy	2023-05-03	criteria provided, single submitter	clinical testing	Variant summary: LAMA2 c.5325dupA (p.Leu1776ThrfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251280 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5325dupA has been reported in the literature in at least two compound heterozygous individuals affected with Laminin Alpha 2-Related Dystrophy (e.g., Geranmayeh_2010, Oliveira_2018). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20207543, 30055037). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000666437	SCV005059879	pathogenic	Merosin deficient congenital muscular dystrophy	2024-03-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV004792362	SCV005413753	pathogenic	not provided	2023-09-15	criteria provided, single submitter	clinical testing	PM2_moderate, PM3, PVS1
PreventionGenetics, part of Exact Sciences	RCV004533466	SCV004750527	pathogenic	LAMA2-related disorder	2024-02-15	no assertion criteria provided	clinical testing	The LAMA2 c.5325dupA variant is predicted to result in a frameshift and premature protein termination (p.Leu1776Thrfs*3). This variant has been reported to be causative for autosomal recessive merosin-deficient congenital muscular dystrophy 1A (MCD1A) (Geranmayeh et al. 2010. PubMed ID: 20207543). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in LAMA2 are expected to be pathogenic. This variant is interpreted as pathogenic.