Submissions for variant NM_001448.3(GPC4):c.772C>T (p.Arg258Trp)

gnomAD frequency: 0.00060  dbSNP: rs199910189

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004036735	SCV004877244	uncertain significance	Inborn genetic diseases	2022-10-31	criteria provided, single submitter	clinical testing	The c.772C>T (p.R258W) alteration is located in exon 4 (coding exon 4) of the GPC4 gene. This alteration results from a C to T substitution at nucleotide position 772, causing the arginine (R) at amino acid position 258 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355306	SCV001550158	uncertain significance	not provided		no assertion criteria provided	clinical testing	The GPC4 p.Arg258Trp variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs199910189) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 89 of 205024 chromosomes (38 hemizygous) at a frequency of 0.0004341 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 81 of 92419 chromosomes (freq: 0.0008764), Other in 2 of 5329 chromosomes (freq: 0.0003753), African in 4 of 19047 chromosomes (freq: 0.0002100) and Latino in 2 of 28045 chromosomes (freq:0.00007131), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. Although the p.Arg258 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. 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 greater than 10% 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001355306	SCV002034961	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001355306	SCV002035403	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003908542	SCV004727343	likely benign	GPC4-related disorder	2021-09-07	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).