Submissions for variant NM_018249.6(CDK5RAP2):c.4039C>G (p.Leu1347Val)

gnomAD frequency: 0.00057  dbSNP: rs144012972

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001733401	SCV001983647	uncertain significance	not specified	2021-09-28	criteria provided, single submitter	clinical testing	Variant summary: CDK5RAP2 c.4039C>G (p.Leu1347Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251478 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4039C>G in individuals affected with Primary Autosomal Recessive Microcephaly 3 and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002539829	SCV003285656	uncertain significance	not provided	2022-03-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1347 of the CDK5RAP2 protein (p.Leu1347Val). This variant is present in population databases (rs144012972, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CDK5RAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1301368). 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 tolerated. 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.
CeGaT Center for Human Genetics Tuebingen	RCV002539829	SCV004700519	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CDK5RAP2: BP4
Ambry Genetics	RCV004968241	SCV005561740	likely benign	Inborn genetic diseases	2024-07-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.