Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none

GenCC - Strong by Invitae, limited by Ambry

Not in BabySeq

HGMD curated below

Clinical Validity Scoring Notes and points

Instead of fully curating this GDA, I just looked for evidence of LOF mechanism based on c.386G>A p.W129* variant found in SDSM-EAW:

• Variant has high frequency for a presumed AD disorder, 0.001084 (116/91094) in South Asian grpmax chromosomes. Prevalence of erythrokeratodermia variabilis is unknown according to orphanet, so considering that this is a rare disorder, this variant is too high, and I would apply BS1. Gene is not LOF constrained. Variant not found via google scholar. It is present in HGMD but reported in a carrier screening study only (PMID 31589614). Reviewing LOF variants in ClinVar, there are several LOF variants interpreted as benign or LB by reputable labs (Invitae / GeneDx): (Variation ID 1276227, 195421, 1276227). Looked for LOF variants in HGMD - there are no DM variants, and some are the same B/LB variants in ClinVar. Given this info, I am not convinced by the P/LP submissions in ClinVar for this variant, and in fact the submitters do not provide any evidence summaries or clinical info. Did not review further, at most this is a VUS, but given frequency LB is appropriate.

Clinical Validity Points Total

Source:

Clinical Validity Classification

Source:

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

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

Case ID, Curator name, Date, Jira ticket link