Genetic Variant CRLS1:p.Leu217Phe (chr20-6031359-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_019095.6(CRLS1):c.649C>T(p.Leu217Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000758 in 1,451,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

CRLS1
NM_019095.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.39

Publications

1 publications found

Variant links:

Genes affected

CRLS1 (HGNC:16148): (cardiolipin synthase 1) This gene encodes a member of the CDP-alcohol phosphatidyltransferase class-I family of proteins. The encoded enzyme catalyzes the synthesis of cardiolipin, a phospholipid component of mitochondrial membranes that is critical for mitochondrial function. [provided by RefSeq, Apr 2016]

CRLS1 Gene-Disease associations (from GenCC):

combined oxidative phosphorylation deficiency 57
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

CRLS1 links:

ENSG00000286235 (HGNC:):

ENSG00000286235 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-6031359-C-T is Pathogenic according to our data. Variant chr20-6031359-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2443705.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019095.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRLS1	NM_019095.6	MANE Select	c.649C>T	p.Leu217Phe	missense	Exon 4 of 7	NP_061968.1	Q9UJA2-1
CRLS1	NM_001127458.2		c.352C>T	p.Leu118Phe	missense	Exon 4 of 7	NP_001120930.1	Q9UJA2-2
CRLS1	NM_001323561.2		c.316C>T	p.Leu106Phe	missense	Exon 4 of 7	NP_001310490.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRLS1	ENST00000378863.9	TSL:1 MANE Select	c.649C>T	p.Leu217Phe	missense	Exon 4 of 7	ENSP00000368140.4	Q9UJA2-1
ENSG00000286235	ENST00000652720.1		c.2773C>T	p.Leu925Phe	missense	Exon 21 of 24	ENSP00000498784.1	A0A494C100
CRLS1	ENST00000452938.5	TSL:1	c.575-653C>T		intron	N/A	ENSP00000416770.1	Q6NTG3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000163

AC:

AN:

245604

AF XY:

0.0000226

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:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000758

AC:

AN:

1451436

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

721992

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33194

American (AMR)

AF:

0.00

AC:

AN:

43490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39440

South Asian (SAS)

AF:

0.00

AC:

AN:

84256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000994

AC:

AN:

1106114

Other (OTH)

AF:

0.00

AC:

AN:

60024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined oxidative phosphorylation deficiency 57 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.0075

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.0070

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.9

PhyloP100

4.4

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.22

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.61

MutPred

0.57

Gain of helix (P = 0.132)

MVP

0.61

MPC

0.57

ClinPred

0.78

GERP RS

5.8

Varity_R

0.45

gMVP

0.85

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over