rs863225445

Variant names:

• chr2-43934197-ATCT-A
• rs863225445
• NM_133259.4:c.2726_2728delAGA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_133259.4(LRPPRC):​c.2726_2728delAGA​(p.Lys909del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRPPRC NM_133259.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.90
• Publications: 1 publications found

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]

LRPPRC Gene-Disease associations (from GenCC):

• congenital lactic acidosis, Saguenay-Lac-Saint-Jean type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_133259.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-43934197-ATCT-A is Pathogenic according to our data. Variant chr2-43934197-ATCT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 218167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133259.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRPPRC	NM_133259.4	MANE Select	c.2726_2728delAGA	p.Lys909del	disruptive_inframe_deletion	Exon 25 of 38	NP_573566.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRPPRC	ENST00000260665.12	TSL:1 MANE Select	c.2726_2728delAGA	p.Lys909del	disruptive_inframe_deletion	Exon 25 of 38	ENSP00000260665.7
	LRPPRC	ENST00000683125.1		c.2726_2728delAGA	p.Lys909del	disruptive_inframe_deletion	Exon 25 of 39	ENSP00000507939.1
	LRPPRC	ENST00000683220.1		c.2756_2758delAGA	p.Lys919del	disruptive_inframe_deletion	Exon 25 of 38	ENSP00000507151.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=62/38	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863225445; hg19: chr2-44161336;