Submissions for variant NM_005562.3(LAMC2):c.599C>A (p.Ala200Glu)

gnomAD frequency: 0.00042  dbSNP: rs138266625

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000916881	SCV001062136	benign	not provided	2024-03-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001102369	SCV001259039	uncertain significance	Junctional epidermolysis bullosa	2018-01-13	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.
CeGaT Center for Human Genetics Tuebingen	RCV000916881	SCV004123939	likely benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	LAMC2: BP4, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000916881	SCV001553130	uncertain significance	not provided		no assertion criteria provided	clinical testing	The LAMC2 p.Ala200Glu variant was not identified in the literature but was identified in dbSNP (ID: rs138266625) and ClinVar (classified as benign by Invitae). The variant was identified in control databases in 214 of 282842 chromosomes at a frequency of 0.0007566 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 49 of 30616 chromosomes (freq: 0.0016), Latino in 48 of 35440 chromosomes (freq: 0.001354), Other in 9 of 7224 chromosomes (freq: 0.001246), European (non-Finnish) in 103 of 129150 chromosomes (freq: 0.000798), Ashkenazi Jewish in 2 of 10366 chromosomes (freq: 0.000193) and African in 3 of 24970 chromosomes (freq: 0.00012), but was not observed in the East Asian, or European (Finnish) populations. The p.Ala200 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. 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003913069	SCV004745711	likely benign	LAMC2-related disorder	2023-12-26	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).