Submissions for variant NM_015272.5(RPGRIP1L):c.2399A>C (p.Asn800Thr)

gnomAD frequency: 0.00026  dbSNP: rs147734438

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000816131	SCV000956624	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 800 of the RPGRIP1L protein (p.Asn800Thr). This variant is present in population databases (rs147734438, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with RPGRIP1L-related conditions. ClinVar contains an entry for this variant (Variation ID: 659168). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RPGRIP1L protein function. 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.
Illumina Laboratory Services, Illumina	RCV001115724	SCV001273723	uncertain significance	Meckel syndrome, type 5	2018-01-13	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	RCV001115725	SCV001273724	uncertain significance	Joubert syndrome 7	2018-01-13	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	RCV001115726	SCV001273725	uncertain significance	Nephronophthisis 8	2018-01-13	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.
GeneDx	RCV001551190	SCV001771648	uncertain significance	not provided	2021-11-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002487798	SCV002777569	uncertain significance	Joubert syndrome 7; Meckel syndrome, type 5; COACH syndrome 3	2022-03-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002537403	SCV003760823	uncertain significance	Inborn genetic diseases	2022-02-11	criteria provided, single submitter	clinical testing	The c.2399A>C (p.N800T) alteration is located in exon 17 (coding exon 16) of the RPGRIP1L gene. This alteration results from a A to C substitution at nucleotide position 2399, causing the asparagine (N) at amino acid position 800 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001551190	SCV003811896	uncertain significance	not provided	2021-08-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003424357	SCV004117256	uncertain significance	RPGRIP1L-related condition	2023-11-29	criteria provided, single submitter	clinical testing	The RPGRIP1L c.2399A>C variant is predicted to result in the amino acid substitution p.Asn800Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.040% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV001825641	SCV002085696	uncertain significance	Familial aplasia of the vermis	2020-02-03	no assertion criteria provided	clinical testing