Submissions for variant NM_133259.4(LRPPRC):c.3430C>T (p.Arg1144Cys)

gnomAD frequency: 0.00009  dbSNP: rs760016065

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000673209	SCV000430602	uncertain significance	Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type	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.
Counsyl	RCV000673209	SCV000798386	uncertain significance	Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type	2018-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002230704	SCV002511920	uncertain significance	not specified	2022-04-25	criteria provided, single submitter	clinical testing	Variant summary: LRPPRC c.3430C>T (p.Arg1144Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251402 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in LRPPRC causing Leigh Syndrome, French-Canadian Type (0.00014 vs 0.0005), allowing no conclusion about variant significance. c.3430C>T has been reported in the literature as a non-informative genotype (phase/co-segregation/zygosity/genotype not clearly specified) in at-least two reports of an individual affected with mild Leigh Syndrome, outside of Quebec (example, Xinyang Han_2017) and in an individual with hypertrophic cardiomyopathy (HCM) who underwent a multigene panel analysis (example, Chung_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Leigh Syndrome, French-Canadian Type. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.