ClinVar Miner

Submissions for variant NM_002335.4(LRP5):c.2234C>T (p.Ala745Val)

gnomAD frequency: 0.00083  dbSNP: rs148550774
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000270488 SCV000329407 uncertain significance not provided 2023-08-28 criteria provided, single submitter clinical testing Reported previously in an individual with familial exudative vitreoretinopathy and was inherited from a parent with mild signs of FEVR (Pefkianaki et al., 2016); Observed in a patient with low bone mineral density in published literature; however, his father who also carried the variant was unaffected (Norwitz et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33716164, 27486893, 30972028, 33118644, 34426522)
Labcorp Genetics (formerly Invitae), Labcorp RCV000270488 SCV001110430 benign not provided 2024-01-18 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000270488 SCV004184168 uncertain significance not provided 2023-11-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004701363 SCV005202887 likely benign not specified 2024-07-23 criteria provided, single submitter clinical testing Variant summary: LRP5 c.2234C>T (p.Ala745Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00095 in 251128 control chromosomes. The observed variant frequency is approximately 15.23 fold of the estimated maximal expected allele frequency for a pathogenic variant in LRP5 causing Familial Exudative Vitreoretinopathy phenotype (6.3e-05). c.2234C>T has been reported in the literature in heterozygous individuals affected with Familial Exudative Vitreoretinopathy or Early-Onset Osteoporosis (Pefkianaki_2016, Norwitz_2019, Sturznickel_2021). These report(s) do not provide unequivocal conclusions about association of the variant with LRP5-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30972028, 27486893, 33716164, 33118644). ClinVar contains an entry for this variant (Variation ID: 279844). Based on the evidence outlined above, the variant was classified as likely benign.

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