Primary lymphoedema

Gene: HGF

Green List (high evidence)

In our local VUS MDT we have started reporting LOF variants in HGF to patients.

Created: 23 Oct 2025, 9:59 a.m. | Last Modified: 23 Oct 2025, 9:59 a.m.

Panel Version: 4.10

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
primary lymphoedema; clinically diverse with variable age of onset; variable degree of lymphoedema but predominantly bilateral in the lower limbs

Publications

• PMID: 18564920
• 40245437
• 38676400
• 38791500

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (>10 unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS update.

Created: 23 Jul 2025, 1:38 p.m. | Last Modified: 23 Jul 2025, 1:38 p.m.

Panel Version: 4.7

PMID:38676400 reported the Brussels PL cohort of 770 primary lymphoedema (PL) patients, of which ten unrelated patients were identified with loss-of-function variants in HGF gene (six nonsense, two frameshift and two splice-site variants). They have not been reported in any disease previously, and only one (p.Arg502Ter) was reported once in GnomAD v3. No likely pathogenic variant was detected in the other known PL genes for these patients. Co-segregation analysis of these variants in available family members identified five additional affected individuals and five unaffected carriers.

In addition, 17 unrelated families were reported with fourteen different rare missense variants in HGF gene. One of the patients carries two HGF missense variants (p.Asn624Lys + p.Gly627Asp), which he inherited from his asymptomatic father. Co-segregation analyses for all likely pathogenic missense variants identified two additional affected carriers and eleven unaffected carriers. There is also functional evidence available for both nonsense and missense variants.

PMID:38791500 reported the identification of a novel heterozygous HGF variant (p.Arg533Ter) in a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern.

Monoallelic variants in HGF gene have not yet been associated with any relevant phenotypes in OMIM or in Gene2Phenotype (records accessed 23 July 2025).

Created: 23 Jul 2025, 1:36 p.m. | Last Modified: 28 Oct 2025, 5:46 p.m.

Panel Version: 4.14

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
primary lymphedema, MONDO:0019175

Publications

• 38676400
• 38791500

Red List (low evidence)

Mode of inheritance
Unknown

Phenotypes
Primary and Secondary Lymphedema

Publications

• 18564920

Four variants reported in four patients with lymphedema. The mode of inheritance has not given.

Created: 24 Jul 2019, 10:30 a.m. | Last Modified: 24 Jul 2019, 10:30 a.m.

Panel Version: 1.87