Submissions for variant NM_025114.4(CEP290):c.4031T>C (p.Val1344Ala)

gnomAD frequency: 0.00067  dbSNP: rs369227219

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177661	SCV000229563	uncertain significance	not provided	2014-05-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001239880	SCV001412783	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1344 of the CEP290 protein (p.Val1344Ala). This variant is present in population databases (rs369227219, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. ClinVar contains an entry for this variant (Variation ID: 196794). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Revvity Omics, Revvity	RCV000177661	SCV003831590	uncertain significance	not provided	2020-04-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000177661	SCV003837178	uncertain significance	not provided	2024-07-10	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV004020112	SCV004926227	uncertain significance	Inborn genetic diseases	2020-09-30	criteria provided, single submitter	clinical testing	The c.4031T>C (p.V1344A) alteration is located in exon 32 (coding exon 31) of the CEP290 gene. This alteration results from a T to C substitution at nucleotide position 4031, causing the valine (V) at amino acid position 1344 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD) database, the CEP290 c.4031T>C alteration was observed in 0.03% (17/65120) of total alleles studied, with a frequency of 0.15% (17/11218) in the African subpopulation. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for the p.V1344A alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001826902	SCV002094240	uncertain significance	Leber congenital amaurosis	2019-10-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004539654	SCV004797778	likely benign	CEP290-related disorder	2022-02-24	no assertion criteria provided	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).