rs912716897

Positions:

• chr2-43918314-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133259.4(LRPPRC):​c.2981G>C​(p.Arg994Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LRPPRC NM_133259.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.0370

Genes affected

LRPPRC (HGNC:15714): (leucine rich pentatricopeptide repeat containing) This gene encodes a leucine-rich protein that has multiple pentatricopeptide repeats (PPR). The precise role of this protein is unknown but studies suggest it may play a role in cytoskeletal organization, vesicular transport, or in transcriptional regulation of both nuclear and mitochondrial genes. The protein localizes primarily to mitochondria and is predicted to have an N-terminal mitochondrial targeting sequence. Mutations in this gene are associated with the French-Canadian type of Leigh syndrome. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19437706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRPPRC	NM_133259.4	c.2981G>C	p.Arg994Thr	missense_variant	28/38	ENST00000260665.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRPPRC	ENST00000260665.12	c.2981G>C	p.Arg994Thr	missense_variant	28/38	1	NM_133259.4	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 27, 2022	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 994 of the LRPPRC protein (p.Arg994Thr). This variant is not present in population databases (gnomAD no frequency). 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: 426849). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2018	The R994T variant in the LRPPRC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R994T variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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 R994T as a variant of uncertain significance. -

Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Feb 21, 2018

This is a 9 year old female with microcephaly, ADHD, intellectual disability, hypertonia, hirsutism, dysmorphic features, bilateral sensorineural hearing loss, prominent nose, mild synophrys, bilateral fifth finger clinodactyly, kyphosis, micrognathia, large ears, midface hypoplasia, Cupid's bow lips, and hypoplastic alae nasi. The p.R994T variant is absent from the gnomAD database. Computational models predict the variant to be benign. A 2nd VUS in the LRPPRC gene was identified but since both parents were not available for testing it is not known if these two variants are in cis or trans. Subsequent clinical testing showed normal brain MRI, lactate, and pyruvate levels, which is not consistent with French-Canadian Leigh syndrome. -

LRPPRC-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2023

The LRPPRC c.2981G>C variant is predicted to result in the amino acid substitution p.Arg994Thr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.17
Sift	Benign	0.049	D
Sift4G	Benign	0.073	T
Polyphen		0.39	B
Vest4		0.43
MutPred		0.49		Loss of helix (P = 0.079);
MVP		0.36
MPC		0.024
ClinPred		0.95	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs912716897; hg19: chr2-44145453;