Submissions for variant NM_000180.4(GUCY2D):c.693G>T (p.Arg231Ser)

dbSNP: rs759280279

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002547609	SCV003492466	uncertain significance	Cone-rod dystrophy 6; Leber congenital amaurosis 1	2022-03-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 231 of the GUCY2D protein (p.Arg231Ser). This variant is present in population databases (rs759280279, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with GUCY2D-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049389). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355420	SCV001550301	uncertain significance	not provided		no assertion criteria provided	clinical testing	The GUCY2D p.Arg231Ser variant was not identified in the literature nor was it identified in the ClinVar, Cosmic, MutDB or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs759280279) and in control databases in 1 of 226088 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: South Asian in 1 of 30284 chromosomes (freq: 0.000033), but not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish) and other populations. The p.Arg231 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, 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. This variant is classified as a variant of uncertain significance.