ENST00000361789.2:c.451T>C

Variant names:

• chrM-15197-T-C
• rs207460001
• ENST00000361789.2:c.451T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.15197T>C (p.S151P) variant in MT-CYTB has been reported in one individual with primary mitochondrial disease to date. This individual had exercise intolerance in early childhood and had the variant present at 80% heteroplasmy in muscle. The variant was undetectable in blood and skin fibroblasts. Complex III activity was reduced at 17% of controls in muscle, 28% in blood, and 50% in skin fibroblasts (PMID:11454242). There are no reports of large families with this variant segregating with disease. There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.72 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120620/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CYB ENST00000361789.2 missense
• Scores: Apogee2 Pathogenic 0.91
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 EXIT
• Conservation: PhyloP100: 4.60
• Publications: 9 publications found

Genes affected

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CYB Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leber hereditary optic neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTB	unassigned_transcript_4818	c.451T>C	p.Ser151Pro	missense_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CYB	ENST00000361789.2	c.451T>C	p.Ser151Pro	missense_variant	Exon 1 of 1	6		ENSP00000354554.2

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): EXIT

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Exercise intolerance Pathogenic:1

Jul 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Jan 08, 2024

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.15197T>C (p.S151P) variant in MT-CYTB has been reported in one individual with primary mitochondrial disease to date. This individual had exercise intolerance in early childhood and had the variant present at 80% heteroplasmy in muscle. The variant was undetectable in blood and skin fibroblasts. Complex III activity was reduced at 17% of controls in muscle, 28% in blood, and 50% in skin fibroblasts (PMID: 11454242). There are no reports of large families with this variant segregating with disease. There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.72 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.91
Hmtvar	Pathogenic	0.89
AlphaMissense	Pathogenic	0.86
PhyloP100		4.6
Mutation Taster		=60/40	polymorphism

Other links and lift over

dbSNP: rs207460001; hg19: chrM-15198;