Submissions for variant NM_000426.4(LAMA2):c.4876C>T (p.Gln1626Ter)

gnomAD frequency: 0.00002  dbSNP: rs369776766

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536256	SCV000658692	pathogenic	LAMA2-related muscular dystrophy	2023-08-31	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs369776766, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Gln1626*) 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 has not been reported in the literature in individuals affected with LAMA2-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 477476).
New York Genome Center	RCV002227483	SCV002506725	likely pathogenic	Merosin deficient congenital muscular dystrophy; Muscular dystrophy, limb-girdle, autosomal recessive 23	2021-06-22	criteria provided, single submitter	clinical testing	The heterozygous c.4876C>T (p.Gln1626Ter) stop-gained variant identified in exon 34 (of 65) of the LAMA2 gene has not been reported in affected individuals in theliterature. The variant creates a premature translation termination codon and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant has been reported in the ClinVar database [Variation ID: 477476]. The variant has 0.00001971 allele frequency in the gnomAD(v3) database (3 out of 152206 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. Based on the available evidence, the heterozygous c.4876C>T (p.Gln1626Ter) stop-gained variant identified in the LAMA2 gene is reported as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000536256	SCV002766030	likely pathogenic	LAMA2-related muscular dystrophy	2022-11-17	criteria provided, single submitter	clinical testing	Variant summary: LAMA2 c.4876C>T (p.Gln1626X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250824 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4876C>T in individuals affected with Laminin Alpha 2-Related Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as either pathogenic (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003470796	SCV004190457	likely pathogenic	Merosin deficient congenital muscular dystrophy	2024-03-04	criteria provided, single submitter	clinical testing