ClinVar Miner

Submissions for variant NM_133259.4(LRPPRC):c.1061C>T (p.Ala354Val) (rs119466000)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003257 SCV000792743 pathogenic Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type 2017-07-11 criteria provided, single submitter clinical testing
Invitae RCV000796281 SCV000935787 pathogenic not provided 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 354 of the LRPPRC protein (p.Ala354Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs119466000, ExAC 0.007%). This variant has been described as a founder variant for Leigh syndrome in the French-Canadian population (PMID: 12529507, 21266382). ClinVar contains an entry for this variant (Variation ID: 3110). Experimental studies have shown that this missense change reduces LRPPRC protein trafficking to mitochondria (PMID: 15139850). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000003257 SCV001437300 pathogenic Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type 2020-09-17 criteria provided, single submitter clinical testing Variant summary: LRPPRC c.1061C>T (p.Ala354Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251350 control chromosomes. c.1061C>T has been reported in the literature in many individuals affected with Leigh Syndrome, French-Canadian Type (examples- Mootha_2003, Debray_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that fibroblasts from patients homozygous for the variant demonstrated reduced levels of COX enzyme activity and a reduction in the synthesis of mitochondrial COX subunits (Sasarman_2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000796281 SCV001788616 pathogenic not provided 2021-03-01 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20200222, 17050673, 15139850, 12529507, 21266382, 25214534)
OMIM RCV000003257 SCV000023415 pathogenic Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type 2003-01-21 no assertion criteria provided literature only
Natera, Inc. RCV000003257 SCV001452503 pathogenic Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type 2020-09-16 no assertion criteria provided clinical testing

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