Submissions for variant NM_133259.4(LRPPRC):c.1253A>C (p.Asn418Thr)

dbSNP: rs373908553

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523785	SCV000618079	uncertain significance	not provided	2017-09-29	criteria provided, single submitter	clinical testing	The N418T variant in the LRPPRC gene has been reported previously in an individual with a lethal infantile mitochondrial disorder who was heterozygous for N418T and another LRPPRC variant, however segregation information was not provided (Kohda et al., 2016). The N418T variant is observed in 6/9836 (0.06%) alleles from individuals of Ashkenazi Jewish background, in the gnomAD dataset (Lek et al., 2016). The N418T 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 not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N418T as a variant of uncertain significance.
Counsyl	RCV000667875	SCV000792387	uncertain significance	Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type	2017-06-22	criteria provided, single submitter	clinical testing
Invitae	RCV000523785	SCV003524753	uncertain significance	not provided	2022-05-16	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 418 of the LRPPRC protein (p.Asn418Thr). This variant is present in population databases (rs373908553, gnomAD 0.06%). This missense change has been observed in individual(s) with LRPPRC-related conditions (PMID: 26741492). ClinVar contains an entry for this variant (Variation ID: 449720). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323585	SCV004029858	uncertain significance	not specified	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: LRPPRC c.1253A>C (p.Asn418Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251158 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1253A>C has been reported in the literature in an individual affected with childhood onset mitochondrial respiratory chain deficiency (example: Kohda_2016). 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. The following publication has been ascertained in the context of this evaluation (PMID: 26741492). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000667875	SCV002076566	uncertain significance	Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type	2020-07-05	no assertion criteria provided	clinical testing