NM_018384.5(GIMAP5):c.611T>C (p.Leu204Pro) AND Portal hypertension, noncirrhotic, 2

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 4, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001548746.4

Allele description [Variation Report for NM_018384.5(GIMAP5):c.611T>C (p.Leu204Pro)]

NM_018384.5(GIMAP5):c.611T>C (p.Leu204Pro)

Genes:

GIMAP1-GIMAP5:GIMAP1-GIMAP5 readthrough [Gene - HGNC]
GIMAP5:GTPase, IMAP family member 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_018384.5(GIMAP5):c.611T>C (p.Leu204Pro)

Other names:

GIMAP5, LEU204PRO (rs72650695); L204P

HGVS:

NC_000007.14:g.150742750T>C
NM_001199577.2:c.1223T>C
NM_001303630.2:c.839T>C
NM_018384.5:c.611T>CMANE SELECT
NP_001186506.1:p.Leu408Pro
NP_001290559.1:p.Leu280Pro
NP_060854.2:p.Leu204Pro
NC_000007.13:g.150439838T>C

Protein change:

L280P; LEU204PRO

Links:

OMIM: 608086.0004; dbSNP: rs72650695

NCBI 1000 Genomes Browser:

rs72650695

Molecular consequence:

NM_001199577.2:c.1223T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001303630.2:c.839T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_018384.5:c.611T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Portal hypertension, noncirrhotic, 2
Identifiers:: MONDO: MONDO:0030397; MedGen: C5561948; OMIM: 619463

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001768715	OMIM	no assertion criteria provided	Pathogenic (Aug 2, 2021)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 33956074, 29382851
SCV004175809	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004804153	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 35753512, 33956074, 29382851 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001768715

OMIM

no assertion criteria provided

Pathogenic
(Aug 2, 2021)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV004175809

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 14, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004804153

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 4, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

Similuk MN, Yan J, Ghosh R, Oler AJ, Franco LM, Setzer MR, Kamen M, Jodarski C, DiMaggio T, Davis J, Gore R, Jamal L, Borges A, Gentile N, Niemela J, Lowe C, Jevtich K, Yu Y, Hullfish H, Hsu AP, Hong C, Littel P, et al.

J Allergy Clin Immunol. 2022 Oct;150(4):947-954. doi: 10.1016/j.jaci.2022.06.009. Epub 2022 Jun 24. Review.

PubMed [citation]

PMID:: 35753512
PMCID:: PMC9547837

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV001768715.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a 21-year-old man, born of unrelated parents (kindred 4), with noncirrhotic portal hypertension-2 (NCPH2; 619463), Drzewiecki et al. (2021) identified a homozygous mutation in the GIMAP5 gene, resulting in a leu204-to-pro (L204P) substitution at a moderately conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was present at a low frequency (2.1 x 10(-3)) in the gnomAD database. The authors stated that the mutation led to loss of GIMAP5 protein expression. Functional studies of the variant were not performed, but it was predicted to result in a loss of protein function. The mutations in this patient had previously been reported by Patterson et al. (2018), who found undetectable protein expression in both GIMP5 isoforms.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004175809.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The missense c.611T>C (p.Leu204Pro) in GIMAP5 gene has been reported previously in homozygous state in individuals affected with GIMAP5-associated hypertension (Patterson et al. 2018; Drzewiecki et al. 2021). Experimental studies demonstrated an undetectable protein expression of both GIMAP5 isoforms for this variant (Patterson et al. 2018). This variant is reported with an allele frequency of 0.2% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic. The amino acid change p.Leu204Pro in GIMAP5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 204 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004804153.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: GIMAP5 c.611T>C (p.Leu204Pro) results in a non-conservative amino acid change located in the AIG1-type guanine nucleotide-binding (G) domain (IPR006703) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 251010 control chromosomes in the gnomAD database, including 1 homozygotes. c.611T>C has been reported in the literature in a homozygous individuals affected with GIMAP5-associated hypertension. T cells isolated from this patient had complete loss of GIMAP5 protein expression, reduced T cell proliferation which was restored upon pharmacological targeting of GSK3. (example: Patterson_2018, and Drewieck_GIMAP5_JEM_2021). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33956074, 29382851, 35753512).Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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