Submissions for variant NM_001101426.4(CRPPA):c.895G>C (p.Gly299Arg)

dbSNP: rs373890080

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413556	SCV000492311	uncertain significance	not specified	2016-12-08	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ISPD gene. The G299R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G299R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G299R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000819341	SCV000959995	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7; Autosomal recessive limb-girdle muscular dystrophy type 2U	2022-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 299 of the ISPD protein (p.Gly299Arg). This variant is present in population databases (rs373890080, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with ISPD-related conditions. ClinVar contains an entry for this variant (Variation ID: 373694). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000998769	SCV001155041	uncertain significance	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000998769	SCV003815684	uncertain significance	not provided	2020-10-06	criteria provided, single submitter	clinical testing