Gene-disease assertions not curated here (add link or write note): Curating for LOF variant association for case SDSM-NR3 in association with cardiac disorders only.

Disease

Curating for LOF variant association for case SDSM-NR3 in association with cardiac disorders

Inheritance

Prevalence

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - Limited for AD dilated cardiomyopathy. GenCC - Strong / Moderate for AD atrial conduction disease by Invitae and Ambry, respectively.

Clinical Validity Scoring Notes and points

Clinical Validity Points Total

Reviewed HGMD for truncating variants:

PMID: 32529721

  • c.1441C>T p.R481* present in several populations in gnomAD v4, highest of 0.0025% (5/74632) in African / African American.

    • Reported in a family with cardiac conduction defects (complete right bundle branch block, atrioventricular block, atrial tachycardia). Variant found via WES proband-only. Variant segregated in 2 other affected relatives. No points due to frequency in gnomAD.

PMID: 31345219

  • c.1171G>T p.E391* - DM?, reported in Supplementary Table 1. [B:1:74819807:G:T:hg19], no specific phenotypes provided

PMID: 29355681

  • c.333+2T>C, 2 alleles gnomAD v4, SpliceAI: 0.980

    • variant found in a proband with cardiac conduction abnormality and syncope, segregated in an uncle with CCM (per the clingen curation, I couldn’t get access to the full text). Not awarding any segregation evidence. 1 POINT FOR COMMON DISEASE (CARDIAC CONDUCTION DEFECT), LOF variant.

PMID: 32746448

  • c.1437delA, p.G480Dfs*7 in supplement, classified as VUS found in proband with DCM. In 11 African/African American alleles in gnomAD. No points awarded.

  • Deletion arr[hg19] 1p31.1(74,696,439-74,797,140)x0, classified as VUS found in proband with HCM. Max of 1 point (HCM)

Did not review

  • c.193G>T p.E65* reported in PMID: 31847883 - DM? and unexplained death is not specific enough, per HGMD “Likely Pathogenic. Molecular Autopsy (MA) study. p.Glu179* in FPGT-TNNI3K in Table S3B.”

  • c.2084C>A p.S695* - DM? for autism

  • c.1437delA p.(Gly480Aspfs*7) - DM? for cardiomyopathy dilated, modifier of in PMID: 32746448

  • c.933-1G>T DM? associated with developmental and epileptic encephalopathy in PMID: 31175295

  • c.956_966dup11 p.(Lys323Leufs*3) DM? for unexplained cardiac arrest in PMID: 35352813 [Classified as VUS]. See supplementary table 5. [B:1:74818972:A:ATTGACCTAGTC:hg19:c.955_956insTTGACCTAGTC:p.I319fs]

Source:

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Not evaluated

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Unknown - no sufficient evidence to say it is LOF.

  • No convincing evidence from HGMD scoring (see above)

  • ClinVar - 41 nonsense variants, all but 1 are classified as VUS. NM_015978.3(TNNI3K):c.2222C>A (p.Ser741Ter) cites Liu et al., 2020 to support LOF mechanism.

  • Gene is not LOF constrained w/ loeuf 1.4

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

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

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

- 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

SDSM-NR3, ANDREA OZA, 03.18.2025