2-27312589-C-G

Variant names:

• chr2-27312589-C-G
• rs267607257
• NM_002437.5:c.280G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_002437.5(MPV17):​c.280G>C​(p.Gly94Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G94E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MPV17 NM_002437.5 missense, splice_region
• Scores: Splicing: ADA: 0.2117
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.12
• Publications: 8 publications found

Genes affected

MPV17 (HGNC:7224): (mitochondrial inner membrane protein MPV17) This gene encodes a mitochondrial inner membrane protein that is implicated in the metabolism of reactive oxygen species. Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDDS). [provided by RefSeq, Jul 2008]

MPV17 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Charcot-Marie-Tooth disease, axonal, type 2EE

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_002437.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-27312589-C-G is Pathogenic according to our data. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27312589-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1810247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPV17	NM_002437.5	c.280G>C	p.Gly94Arg	missense_variant, splice_region_variant	Exon 5 of 8	ENST00000380044.6	NP_002428.1
MPV17	XM_005264326.5	c.280G>C	p.Gly94Arg	missense_variant, splice_region_variant	Exon 5 of 8		XP_005264383.1
MPV17	XM_017004151.2	c.232G>C	p.Gly78Arg	missense_variant, splice_region_variant	Exon 5 of 8		XP_016859640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPV17	ENST00000380044.6	c.280G>C	p.Gly94Arg	missense_variant, splice_region_variant	Exon 5 of 8	1	NM_002437.5	ENSP00000369383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461668 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome Pathogenic:1

Jan 21, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MPV17 c.280G>C (p.Gly94Arg) results in a non-conservative amino acid change located in the inner mitochondrial membrane domain (Baumann_2019) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251248 control chromosomes. c.280G>C has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with supportive clinical and biochemical features of Mitochondrial DNA Depletion Syndrome - MPV17 Related (example, PMID: 20074988 with subsequent citations by others). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Dec 17, 2022

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease, axonal, type 2EE Pathogenic:1

Aug 11, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.0090	T
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.59	D
PhyloP100		4.1
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Vest4		0.36
MutPred		0.22		Loss of glycosylation at S81 (P = 0.0319);
MVP		0.56
ClinPred		0.96	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.074
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.21
dbscSNV1_RF	Benign	0.55
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: 0

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

Other links and lift over

dbSNP: rs267607257; hg19: chr2-27535456;