Submissions for variant NM_016341.4(PLCE1):c.1927G>T (p.Ala643Ser)

dbSNP: rs61886330

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516190	SCV000614586	uncertain significance	not specified	2016-12-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000891403	SCV001035219	likely benign	not provided	2024-12-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001108876	SCV001266163	uncertain significance	Nephrotic syndrome, type 3	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	RCV000891403	SCV005893771	likely benign	not provided	2025-01-01	criteria provided, single submitter	clinical testing	PLCE1: BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000891403	SCV001552485	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PLCE1 p.Ala643Ser variant was identified in the literature in 1 of 69 families with focal and segmental glomerulosclerosis (Gbadegesin_2009_PMID:18975016). The variant was identified in dbSNP (ID: rs61886330), ClinVar (classified as uncertain significance by Athena Diagnostics Inc) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 383 of 280922 chromosomes (1 homozygous) at a frequency of 0.001363 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 (Finnish) in 63 of 25038 chromosomes (freq: 0.002516), Other in 15 of 7146 chromosomes (freq: 0.002099), European (non-Finnish) in 270 of 128664 chromosomes (freq: 0.002098), South Asian in 16 of 30602 chromosomes (freq: 0.000523), Ashkenazi Jewish in 4 of 10360 chromosomes (freq: 0.000386), Latino in 13 of 35376 chromosomes (freq: 0.000368) and African in 2 of 24200 chromosomes (freq: 0.000083), but was not observed in the East Asian population. The p.Ala643 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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	RCV003900076	SCV004708779	likely benign	PLCE1-related disorder	2021-08-11	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).