Submissions for variant NM_005562.3(LAMC2):c.493C>T (p.Arg165Cys)

gnomAD frequency: 0.00261  dbSNP: rs142335339

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000270360	SCV000345142	likely benign	not specified	2016-08-22	criteria provided, single submitter	clinical testing
Invitae	RCV000950067	SCV001096345	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001100402	SCV001256921	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Reference Center For Rare Oral And Dental Diseases, Crmr O-rares, Hôpitaux Universitaires De Strasbourg	RCV003153552	SCV003842321	uncertain significance	Amelogenesis imperfecta type 1	2023-03-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003967800	SCV004791882	likely benign	LAMC2-related condition	2022-07-14	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000950067	SCV001552130	uncertain significance	not provided		no assertion criteria provided	clinical testing	The LAMC2 p.Arg165Cys variant was not identified in the literature but was identified in dbSNP (ID: rs142335339), ClinVar (classified as likely benign by EGL genetics and Invitae) and LOVD 3.0 (classified as a variant of unknown significance by VKGL-NL). The variant was identified in control databases in 608 of 278704 chromosomes at a frequency of 0.002182 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: European (non-Finnish) in 480 of 125956 chromosomes (freq: 0.003811), Other in 18 of 7128 chromosomes (freq: 0.002525), Latino in 63 of 35294 chromosomes (freq: 0.001785), African in 25 of 24782 chromosomes (freq: 0.001009), European (Finnish) in 20 of 24942 chromosomes (freq: 0.000802), Ashkenazi Jewish in 1 of 10264 chromosomes (freq: 0.000097) and South Asian in 1 of 30480 chromosomes (freq: 0.000033), but was not observed in the East Asian population. The p.Arg165 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.