rs794726691

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017775.4(TTC19):c.601_604delGGCT(p.Gly201MetfsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TTC19
NM_017775.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.86

Publications

2 publications found

Variant links:

Genes affected

TTC19 (HGNC:26006): (tetratricopeptide repeat domain 19) This gene encodes a protein with a tetratricopeptide repeat (TPR) domain containing several TPRs of about 34 aa each. These repeats are found in a variety of organisms including bacteria, fungi and plants, and are involved in a variety of functions including protein-protein interactions. This protein is embedded in the inner mitochondrial membrane and is involved in the formation of the mitochondrial respiratory chain III. It has also been suggested that this protein plays a role in cytokinesis. Mutations in this gene cause mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2012]

TTC19 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial complex III deficiency nuclear type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
mitochondrial complex III deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TTC19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-16006489-TGCTG-T is Pathogenic according to our data. Variant chr17-16006489-TGCTG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 102437.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
TTC19	NM_017775.4 link	c.601_604delGGCT	p.Gly201MetfsTer8	frameshift_variant	Exon 7 of 10	ENST00000261647.10	NP_060245.3	Q6DKK2A0A024RD83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TTC19	ENST00000261647.10 link	c.601_604delGGCT	p.Gly201MetfsTer8	frameshift_variant	Exon 7 of 10	1	NM_017775.4	ENSP00000261647.5	Q6DKK2
TTC19	ENST00000475723.5 link	n.285_288delGGCT		non_coding_transcript_exon_variant	Exon 7 of 10	2		ENSP00000465754.1	K7EKS0
TTC19	ENST00000497842.6 link	n.711_714delGGCT		non_coding_transcript_exon_variant	Exon 6 of 10	5
TTC19	ENST00000475723.5 link	n.285_288delGGCT		3_prime_UTR_variant	Exon 7 of 10	2		ENSP00000465754.1	K7EKS0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251456

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000205

AC:

AN:

1460142

Hom.:

AF XY:

0.00000275

AC XY:

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5590

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110620

Other (OTH)

AF:

0.00

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Nov 02, 2017

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.601_604delGGCT variant in the TTC19 gene has been reported previously in the homozygous and heterozygous states with a second TTC19 variant in association with mitochondrial complex III deficiency; note that c.601_604delGGCT has been reported using alternate nomenclature c.963_966delTGGC and c.964_967delGGCT (Nogueira et al., 2013; Atwal, 2014). The c.601_604delGGCT variant causes a frameshift starting with codon Glycine 201, changes this amino acid to a Methionine residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Gly201MetfsX8. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.601_604delGGCT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.601_604delGGCT as a pathogenic variant. -

Aug 02, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PM2_moderate, PM3, PS3, PVS1 -

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gly201Metfs*8) in the TTC19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TTC19 are known to be pathogenic (PMID: 21278747, 24368687). This variant is present in population databases (rs794726691, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex III deficiency. (PMID: 23532514, 24368687). This variant is also known as p.Gly322MetfsX8 or p.A321Afs*8. ClinVar contains an entry for this variant (Variation ID: 102437). For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial complex III deficiency nuclear type 2

Pathogenic:1

May 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.9

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over