Submissions for variant NM_000426.4(LAMA2):c.1621A>G (p.Ser541Gly)

gnomAD frequency: 0.00175  dbSNP: rs141363186

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000710155	SCV000110608	uncertain significance	not provided	2015-04-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000710155	SCV000329387	likely benign	not provided	2021-01-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000078748	SCV000595512	uncertain significance	not specified	2015-08-21	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710155	SCV000613961	likely benign	not provided	2020-01-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081996	SCV000658631	benign	LAMA2-related muscular dystrophy	2025-02-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001157936	SCV001319542	uncertain significance	Congenital muscular dystrophy due to partial LAMA2 deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mayo Clinic Laboratories, Mayo Clinic	RCV000710155	SCV001713371	uncertain significance	not provided	2022-07-05	criteria provided, single submitter	clinical testing	BP4
CeGaT Center for Human Genetics Tuebingen	RCV000710155	SCV004160278	likely benign	not provided	2025-03-01	criteria provided, single submitter	clinical testing	LAMA2: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078748	SCV005185064	likely benign	not specified	2024-05-22	criteria provided, single submitter	clinical testing	Variant summary: LAMA2 c.1621A>G (p.Ser541Gly) results in a non-conservative amino acid change located in the Laminin IV domain (IPR000034) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 1613948 control chromosomes in the gnomAD database, including 10 homozygotes. The observed variant frequency is approximately 1.19 fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMA2 causing Laminin Alpha 2-Related Dystrophy phenotype (0.0022) suggesting the variant may be benign. c.1621A>G has been reported in the literature in a homozygous and compound heterozygous individual with an unspecified suspected muscular disorder, without evidence of causality (e.g. Thuriot_2020). This report does not provide unequivocal conclusions about association of the variant with Laminin Alpha 2-Related Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32337335). ClinVar contains an entry for this variant (Variation ID: 92939). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV004984669	SCV005607090	likely benign	Inborn genetic diseases	2024-09-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000710155	SCV001550736	likely benign	not provided		no assertion criteria provided	clinical testing	The LAMA2 p.Ser541Gly variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs141363186) and ClinVar (classified as benign by Invitae, likely benign by GeneDx and a VUS by EGL Genetics, Genetics Services Laboratory (University of Chicago) and Athena Diagnostics). The variant was also identified in control databases in 465 of 282658 chromosomes (1 homozygous) at a frequency of 0.001645 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 357 of 129082 chromosomes (freq: 0.002766), Ashkenazi Jewish in 23 of 10368 chromosomes (freq: 0.002218), Other in 10 of 7222 chromosomes (freq: 0.001385), South Asian in 34 of 30616 chromosomes (freq: 0.001111), Latino in 31 of 35400 chromosomes (freq: 0.000876) and African in 10 of 24916 chromosomes (freq: 0.000401), while the variant was not observed in the East Asian and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ser541 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004537311	SCV004725390	likely benign	LAMA2-related disorder	2022-08-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).