Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: HSPA1L

Comment on list classification: This gene was recently promoted to Green and added to the diagnostic panel, however as per review by Zornitza Stark, it has since come to light that several variants reported in patients have a high frequency in the general population, calling into question their pathogenicity. Hence, tagging for GMS expert review to determine whether this gene should be demoted on this panel.

Created: 30 Jul 2025, 3:29 p.m. | Last Modified: 30 Jul 2025, 3:29 p.m.

Panel Version: 8.24

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 26 Sep 2024, 3:34 p.m. | Last Modified: 26 Sep 2024, 3:34 p.m.

Panel Version: 6.10

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

I don't know

The variants identified are present at relatively high frequencies in gnomad V4, in particular p.Thr267Ile is present in 281 individuals, and the p.Ala268Thr is present in 4,753 individuals.

These observations raise concerns about pathogenicity under a monogenic disease model.

Created: 15 Feb 2024, 10:49 p.m. | Last Modified: 15 Feb 2024, 10:49 p.m.

Panel Version: 4.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
inflammatory bowel disease, MONDO:0005265, HSPA1L-related

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (seven unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS review.

Created: 14 Feb 2024, 3:55 p.m. | Last Modified: 14 Feb 2024, 3:55 p.m.

Panel Version: 4.182

As reviewed by Hannah Knight, PMID:28126021 reported the identification of a heterozygous de novo variant (p.Ser277Leu) in HSPA1L in a patient with inflammatory bowel disease. In addition, five additional rare HSPA1L variants (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) were identified in six patients from a cohort of 136 IBD patients with WES data.

Functional studies showed that all six HSPA1L variant proteins showed decreased chaperone activity in vitro. Moreover, three variants demonstrated dominant negative effects on HSPA1L and HSPA1A protein activity.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

Created: 14 Feb 2024, 3:52 p.m. | Last Modified: 14 Feb 2024, 3:52 p.m.

Panel Version: 4.179

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
inflammatory bowel disease, MONDO:0005265

Publications

• 28126021

I don't know

PMID: 28126021 (2017) identified a heterozygous de novo variant (c.830C > T; p.Ser277Leu) in HSPA1L in a patient with IBD + some in vitro testing which supported pathogenicity
Then identified five additional rare HSPA1L variants (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) in six patients from their IBD cohort
Sources: Literature

Created: 13 Feb 2024, 10:26 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Inflammatory bowel disease

Publications

• PMID: 28126021