Submissions for variant NM_153240.5(NPHP3):c.1189C>T (p.Arg397Cys) (rs141477666)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000153593	SCV000203133	likely benign	not specified	2015-09-02	criteria provided, single submitter	clinical testing
Invitae	RCV000168169	SCV000218831	benign	not provided	2019-02-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000153593	SCV000566586	uncertain significance	not specified	2017-06-27	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NPHP3 gene. The R397C variant has been reported previously in two siblings with nephronophthisis; however, a second NPHP3 variant was not identified, and these siblings also had a homozygous deletion in NPHP1 (Hoefele et al., 2007). The R397C variant has also been identified in another individual with nephronophthisis who did not have a second NPHP3 variant identified (Halbritter et al., 2012). A different missense variant at the same position (R397H) has been reported in an individual with nephronophthisis and tapeto-retinal degeneration who did not have a second NPHP3 variant identified (Olbrich et al., 2003). The R379C variant is observed in 42/6614 (0.6%) alleles from individuals of non-Finnish European background, including 1 homozygous individual (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R397C 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 predicts this variant likely does not alter 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.