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Gene-disease assertions not curated here: hypertrophic cardiomyopathy, dilated cardiomyopathy, MYH7-related skeletal myopathy, arrhythmogenic right ventricular cardiomyopathy, congenital heart disease.

Disease

Left Ventricular Non-Compaction

Inheritance

Autosomal dominant

Prevalence

Wide range of prevalence reported, with some suggesting that LVNC is actually a physiological adaptation that can occur in healthy individuals. One study found that prevalence among three healthy control cohorts was 1.05% (95% CI 0.00–7.88; I 2 = 87.95%) and in two non-cardiac patient cohorts was 2.21% (95% CI 0.24–5.46), but found much higher prevalence in cohorts of athletes or pregnant women. They also found a significant difference between prevalence estimates when the method of dx was echo vs. cardiac MRI. (PMID: 31143950)

Another study found that the prevalence in newborns was 0.076% (95% CI, 0.047–0.123) (PMID: 35727876).

Curating as a common disease.

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clinical Validity Scoring Notes and points

PMID: 29447731: study of 327 unrelated patients with non-compaction cardiomyopathy. 45 cardiomyopathy genes were tested. Of the 104 likely genetic cases, MYH7 was the most frequently mutated gene in 19% (n = 10) of children and 11% (n = 29) of adults. 2 children had a pathogenic variant in MYH7 and Ebstein anomaly.

Reported variants (all are LP/P by authors), see supplemental tables 1a and 2a:

  • c.495G>A, p.(Met165Ile) - 1 affected child w/fhx NCCM. P/LP in ClinVar. Absent from GnomAD v4. REVEL = 0.864. (0.1pts)

  • c.689T>C, p.(Phe230Ser) - 1 affected child w/fhx NCCM, pt also had Ebstein anomaly. Absent from GnomAD v4. VUS/LP in ClinVar. REVEL = 0.956. (0.1pts)

  • c.728G>A, p.(Arg243His) - 1 affected child w/fhx NCCM. VUS/LP/P in ClinVar. 2 individuals in GnomAD v4. REVEL: 0.969. (0.1pts)

  • c.732+1G>A, p.(?) - 1 affected child w/fhx NCCM. P/LP in ClinVar. 1 individual in GnomAD v4. Nearest exon is in-frame, NMD-. (0.5pts)

  • c.798T>A, p.(Tyr266*) - 1 affected child w/fhx NCCM. Not in ClinVar. Absent from GnomAD (1 point)

  • c.1106G>A, p.(Arg369Gln) - 1 affected child, no fhx reported. LP by expert panel in ClinVar. They cite (Dellefave 2009 PMID: 20031619; Hoedemaekers 2010 PMID: 20530761; Tian 2015 PMID: 24691700; Li 2018 PMID: 30371277; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm). (0.1pts, could upgrade)

  • c.2713T>C, p.(Cys905Arg) - 1 affected child, w/fhx DCM.

  • c.3113T>C, p.(Leu1038Pro) - 1 affected child w/fhx NCCM, pt also had Ebstein anomaly. 1 affected adult.

  • c.5773C>G, p.(Arg1925Gly) - 1 affected child w/fhx NCCM.

  • c.266A>G, p.(Asp89Gly) -1 affected adult, no fhx reported.

  • c.415G>T, p.(Val139Leu) - 1 affected adult w/fhx NCCM

  • c.715_717delGAC, p.(Asp239del) - 1 affected adult w/fhx NCCM

  • c.689T>C, p.(Phe230Ser) - 1 affected adult w/fhx NCCM

  • c.732+1G>A, p.(?) - 1 affected adult w/fhx NCCM. P/LP in ClinVar. 1 individual in gnomAD v4. Nearest exon is in-frame. (0.5pts)

  • c.847T>G, p.(Tyr283Asp) - 1 affected adult w/fhx NCCM, pt also had Ebstein anomaly

  • c.902T>A, p.(Leu301Gln) - 1 affected adult w/fhx NCCM

  • c.1208G>C, p.(Arg403Pro) - 1 affected adult w/fhx NCCM

  • c.1633G>A, p.(Asp545Asn) and c.2863G>A, p.(Asp955Asn)- 4 affected adults, all carried both variants in cis.

  • c.1915A>G, p.(Lys639Glu) - 1 affected adult w/fhx NCCM

  • c.2085_2097dup, p.(Glu700Glnfs*37) - 1 affected adult, no fhx reported. 4 individuals in GnomAD v4. Not in clinVar. (1pt)

  • c.2678C>T, p.(Ala893Val) - 1 affected adult w/fhx NCCM

  • c.2710C>T, p.(Arg904Cys) - 1 affected adult w/fhx NCCM and DCM

  • c.3100-2A>C, p.(?) - 1 affected adult, no fhx reported.

  • c.4075C>T, p.(Arg1359Cys) - 1 affected adult, no fhx reported.

  • c.4125T>A, p.(Tyr1375*) - 1 affected adult w/fhx ARVC. VUS in ClinVar. 5 individuals in GnomAD v4. (1pt)

  • c.5754C>G, p.(Asn1918Lys) - 6 affected adults, at least one pt had Ebstein anomaly. P in ClinVar. Absent from GnomAD. REVEL: 0.693. (0.6pts)

  • c.5773C>G, p.(Arg1925Gly) - 2 affected adults

PMID: 35527761:

  • c. 3830G>C p.Arg1277Pro - 6mo proband and mother with LVNC. Sequenced 151 genes associated with cardiomyopathy and both mother and child carried this variant, father did not. Other potentially affected family members were not tested. VUS in ClinVar. Variant is absent from GnomAD . REVEL: 0.656. Add 0.1 pts for segregation (0.2pts)

PMID: 25415959:

  • c.1316T>G M439R - 49yo M proband with LVNC and bicuspid aortic valve (BAV). Proband’s son, daughter, and grandson all had the same diagnoses. The variant segregated in the son and grandson, was not tested in the daughter (see fig 1). 27 gene panel. LP by one submitter in ClinVar. Absent from GnomAD. REVEL=0.965. Add 0.2 pts for segregations (0.3pts)

PMID: 18506004: cohort of 63 patients with LVNC. 6 genes evaluated. Same cohort described in PMID: 21551322.

  • c.732+1G>A (described as c.818+1G>A). Family LVNC-101. 4 affected segregations. Variant is P/LP in ClinVar. Also described in PMID: 29447731. Nearest exon is in-frame. (0.5pts)

  • c.728G>A (described as c.814G>A), p.Arg243His. Family LVNC-107. 2 affected segregations. Variant is VUS by expert panel in ClinVar. Also described in PMID: 29447731. (0.1pts)

  • c.818+3G>C

  • c.801_803delGAC p.Asp239del

  • c.840T>C p.Phe252Leu

  • c.4161C>T p.Arg1359Cys

  • c.5296G>A (described as c.5382G>A) p.Ala1766Thr, de novo. Individual MT. VUS/P in ClinVar. Absent from GnomAD v4. REVEL: 0.68. (0.6pts)

PMID: 36292635:

  • c.895+1G>A: 22yo proband and 53 yo father with isolated LVNC. Proband had mitral valve prolapse and heart failure. WGS was conducted on the proband, mother, father, and brother and MYH7 c.895+1G>A was identified in proband and father. Exon 10 is in-frame. Authors hypothesize exon skipping. (0.5pts)

Clinical Validity Points Total

7 points reached, did not curate further.

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

At least moderate.

Source:

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

Clinical Features

LVNC, Ebstein anomaly possible.

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

 Examples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

Case ID, Curator name, Date, Jira ticket link

E3760267114, Areesha Salman, 5/2/24

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