ClinVar Miner

Submissions for variant NM_133259.4(LRPPRC):c.1426A>G (p.Thr476Ala) (rs115507225)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000676635 SCV000251671 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing The T476A variant in the LRPPRC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T476A variant is observed in 245/126,576 (0.19%) alleles from individuals of non-Finnish European background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). The T476A 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret T476A as a variant of uncertain significance.
Invitae RCV000676635 SCV000962827 uncertain significance not provided 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 476 of the LRPPRC protein (p.Thr476Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs115507225, ExAC 0.2%). This variant has not been reported in the literature in individuals with LRPPRC-related disease. ClinVar contains an entry for this variant (Variation ID: 214606). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 Praxis fuer Humangenetik Tuebingen RCV000676635 SCV001249224 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001137663 SCV001297629 uncertain significance Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000676635 SCV000802428 uncertain significance not provided 2016-02-24 no assertion criteria provided clinical testing
Natera, Inc. RCV001137663 SCV001452502 uncertain significance Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type 2020-09-16 no assertion criteria provided clinical testing

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