Submissions for variant NM_133259.4(LRPPRC):c.2966G>A (p.Arg989His)

dbSNP: rs774857058

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198211	SCV000251681	likely pathogenic	not provided	2014-03-03	criteria provided, single submitter	clinical testing	p.Arg989His (CGT>CAT): c.2966 G>A in exon 28 of the LRPPRC gene (NM_133259.3). The R989H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R989H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s).
Illumina Laboratory Services, Illumina	RCV000675141	SCV000430604	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.
Counsyl	RCV000675141	SCV000800731	uncertain significance	Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type	2017-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228880	SCV002511921	uncertain significance	not specified	2022-04-12	criteria provided, single submitter	clinical testing	Variant summary: LRPPRC c.2966G>A (p.Arg989His) 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 8e-06 in 251072 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2966G>A in individuals affected with Leigh Syndrome, French-Canadian Type and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198211	SCV003281434	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 989 of the LRPPRC protein (p.Arg989His). This variant is present in population databases (rs774857058, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with LRPPRC-related conditions. ClinVar contains an entry for this variant (Variation ID: 214616). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LRPPRC protein function. 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.