Submissions for variant NM_000426.4(LAMA2):c.2462C>T (p.Thr821Met)

gnomAD frequency: 0.00173  dbSNP: rs117422805

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000723613	SCV000196850	likely benign	not provided	2020-04-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24611677, 24082139, 27896284, 23891399)
Eurofins Ntd Llc (ga)	RCV000723613	SCV000331387	uncertain significance	not provided	2015-06-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000149994	SCV000595502	uncertain significance	not specified	2016-09-24	criteria provided, single submitter	clinical testing
Invitae	RCV001084610	SCV000658653	benign	LAMA2-related muscular dystrophy	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000670870	SCV000795783	uncertain significance	Merosin deficient congenital muscular dystrophy	2017-11-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001156369	SCV001317862	uncertain significance	Congenital muscular dystrophy due to partial LAMA2 deficiency	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000723613	SCV001500925	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	LAMA2: PM5, BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000149994	SCV002556232	likely benign	not specified	2022-06-29	criteria provided, single submitter	clinical testing	Variant summary: LAMA2 c.2462C>T (p.Thr821Met) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 282674 control chromosomes, predominantly at a frequency of 0.0036 within the Finnish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately two fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.2462C>T has been reported in the literature in at least two homozygous individuals affected with Laminin Alpha 2-Related Dystrophy (example Xiong_2015, Ge_2019, Tan_2021). However, these reports do not provide unequivocal evidence for an association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical-significance assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (VUS n=5, likely benign n=2, benign n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000723613	SCV003808105	likely benign	not provided	2023-09-13	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252050	SCV001427798	likely benign	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing