Submissions for variant NM_015272.5(RPGRIP1L):c.1156A>G (p.Lys386Glu)

gnomAD frequency: 0.00094  dbSNP: rs137982921

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724780	SCV000225033	uncertain significance	not provided	2015-04-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000339807	SCV000397832	uncertain significance	Meckel syndrome, type 5	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	RCV000401583	SCV000397833	uncertain significance	Joubert syndrome 7	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	RCV000307599	SCV000397834	uncertain significance	Nephronophthisis 8	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.
GeneDx	RCV000724780	SCV000567316	uncertain significance	not provided	2018-08-29	criteria provided, single submitter	clinical testing	The K386E variant in the RPGRIP1L gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the K386E variant is observed in 82/66610 (0.23%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The K386E 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. This substitution occurs at a position where amino acids with similar properties to Lysine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K386E as a variant of uncertain significance.
Invitae	RCV000697464	SCV000826076	likely benign	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765297	SCV000896552	uncertain significance	COACH syndrome 1; Joubert syndrome 7; Meckel syndrome, type 5	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002516602	SCV003741897	likely benign	Inborn genetic diseases	2022-08-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000724780	SCV004010485	uncertain significance	not provided	2023-04-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003975263	SCV004787898	likely benign	RPGRIP1L-related condition	2022-02-04	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001271337	SCV001452422	uncertain significance	Familial aplasia of the vermis	2020-04-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000724780	SCV001548640	uncertain significance	not provided		no assertion criteria provided	clinical testing	The RPGRIP1L p.Lys386Glu variant was identified in 1 of 384 proband chromosomes (Frequency: 0.0026) from individuals with nephronophthisis-associated ciliopathy (Halbritter_2012_PMID:23188109). The variant was identified in dbSNP (ID: rs137982921) and ClinVar (classified as uncertain significance by Invitae, EGL Genetic Diagnostics, Fulgent Genetics, GeneDx, and Illumina). The variant was identified in control databases in 228 of 282020 chromosomes at a frequency of 0.0008085 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 54 of 35376 chromosomes (freq: 0.001526), Other in 10 of 7194 chromosomes (freq: 0.00139), European (non-Finnish) in 158 of 128734 chromosomes (freq: 0.001227), Ashkenazi Jewish in 2 of 10354 chromosomes (freq: 0.000193), European (Finnish) in 2 of 24848 chromosomes (freq: 0.00008) and African in 2 of 24964 chromosomes (freq: 0.00008), but was not observed in the East Asian or South Asian populations. The p.Lys386 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.