Submissions for variant NM_153240.5(NPHP3):c.1172C>G (p.Pro391Arg)

gnomAD frequency: 0.00026  dbSNP: rs138982161

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000381270	SCV000441130	uncertain significance	Renal-hepatic-pancreatic dysplasia 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001094792	SCV000441131	uncertain significance	Nephronophthisis 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000346668	SCV000441132	uncertain significance	NPHP3-related Meckel-like syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000291650	SCV000552115	likely benign	Nephronophthisis	2023-11-28	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000728292	SCV000855845	uncertain significance	not provided	2017-07-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002487509	SCV002781086	uncertain significance	Renal-hepatic-pancreatic dysplasia 1; Nephronophthisis 3; NPHP3-related Meckel-like syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002520084	SCV003747689	uncertain significance	Inborn genetic diseases	2022-01-19	criteria provided, single submitter	clinical testing	The c.1172C>G (p.P391R) alteration is located in exon 7 (coding exon 7) of the NPHP3 gene. This alteration results from a C to G substitution at nucleotide position 1172, causing the proline (P) at amino acid position 391 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genetic Services Laboratory, University of Chicago	RCV003151038	SCV003839777	uncertain significance	not specified	2022-08-23	no assertion criteria provided	clinical testing	DNA sequence analysis of the NPHP3 gene demonstrated a sequence change, c.1172C>G, in exon 7 that results in an amino acid change, p.Pro391Arg. This sequence change does not appear to have been previously described in individuals with NPHP3-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.10% in the African subpopulation and 0.0092% in the overall population (dbSNP rs138982161). The p.Pro391Arg change affects a highly conserved amino acid residue located in a domain of the NPHP3 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro391Arg substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro391Arg change remains unknown at this time.