2-43925957-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_133259.4(LRPPRC):c.2741C>A(p.Pro914Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,448,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P914P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: LRPPRC NM_133259.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.19

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRPPRC	NM_133259.4	c.2741C>A	p.Pro914Gln	missense_variant	26/38	ENST00000260665.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRPPRC	ENST00000260665.12	c.2741C>A	p.Pro914Gln	missense_variant	26/38	1	NM_133259.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000152 AC: 22 AN: 1448152 Hom.: 0 Cov.: 27 AF XY: 0.0000166 AC XY: 12 AN XY: 721412

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000555

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 25, 2023

Variant summary: LRPPRC c.2741C>A (p.Pro914Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251188 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2741C>A has been reported in the literature in an individual diagnosed with a lethal infantile mitochondrial disorder (LIMD) (Kohda_2016); however, this report does 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). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.70		Gain of MoRF binding (P = 0.0371);
MVP		0.61
MPC		0.16
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.50

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: rs1463658772; hg19: chr2-44153096; COSMIC: COSV53237724;