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

gnomAD frequency: 0.00334  dbSNP: rs141477666

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153593	SCV000203133	likely benign	not specified	2015-09-02	criteria provided, single submitter	clinical testing
Invitae	RCV000168169	SCV000218831	benign	Nephronophthisis	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001704114	SCV000566586	likely benign	not provided	2020-11-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27392076, 17855640, 23188109)
Illumina Laboratory Services, Illumina	RCV001145350	SCV001306019	uncertain significance	Renal-hepatic-pancreatic dysplasia 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001145351	SCV001306020	uncertain significance	NPHP3-related Meckel-like syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001149669	SCV001310647	uncertain significance	Nephronophthisis 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000153593	SCV002074225	benign	not specified	2022-01-11	criteria provided, single submitter	clinical testing	Variant summary: NPHP3 c.1189C>T (p.Arg397Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 251380 control chromosomes, including 4 homozygotes. The variant was predominantly found within the Non-Finnish European subpopulation at a frequency of 0.005. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 12-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in NPHP3 causing Joubert Syndrome and Related Disorders phenotype (0.0004), strongly suggesting that the variant is a benign polymorphism. c.1189C>T has been reported in the literature in the heterozygous state in individuals affected with retinal- or renal dysorders (e.g. Tiwari_2016, Arno_2017, Hoefele_2007), however in these cases other (potentially) pathogenic variants were also described, including a homozygous deletion variant in NPHP1 that was found in two siblings affected with nephronophthisis (Hoefele_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed this variant since 2014: one submitter classified the variant as of uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign.