CRLS1

Chr 20AR

cardiolipin synthase 1

Also known as: C20orf155, CLS, CLS1, COSPD57, GCD10, dJ967N21.6

NCBI Gene: 54675 ENSG00000088766 UniProt: Q9UJA2 OMIM: 608188

The enzyme catalyzes the synthesis of cardiolipin, a critical phospholipid component of mitochondrial membranes essential for maintaining mitochondrial functional integrity and dynamics. Mutations cause combined oxidative phosphorylation deficiency 57, following an autosomal recessive inheritance pattern. The gene shows tolerance to loss-of-function variants (low constraint), which is consistent with the recessive disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.931 OMIM phenotype

Clinical Summary— CRLS1

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 38 VUS of 60 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.93LOEUF

pLI 0.003

Z-score 1.74

OE 0.47 (0.26–0.93)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.47Z-score

OE missense 0.88 (0.74–1.03)

100 obs / 114.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.26–0.93)

0≤0.351.4

Missense OE?0.88 (0.74–1.03)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 6 / 12.7Missense obs/exp: 100 / 114.2Syn Z: 0.62

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCRLS1-related mitochondrial disorderOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.81top 10%

GOF

0.6444th %ile

LOF

0.2969th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

60 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

VUS38

Likely Benign6

Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	2	0	5
Likely Pathogenic	0	0	0	0
VUS	38	0	0	38
Likely Benign	2	1	3	6
Benign	0	0	0	0
Total	43	3	3	49

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

28 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap CRLS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →