NM_000410.4(HFE):c.884T>C (p.Val295Ala) AND Hemochromatosis type 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 20, 2023
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:: RCV001152293.7

Allele description [Variation Report for NM_000410.4(HFE):c.884T>C (p.Val295Ala)]

NM_000410.4(HFE):c.884T>C (p.Val295Ala)

Gene:

HFE:homeostatic iron regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p22.2

Genomic location:

Preferred name:

NM_000410.4(HFE):c.884T>C (p.Val295Ala)

HGVS:

NC_000006.12:g.26092952T>C
NG_008720.2:g.10672T>C
NM_000410.4:c.884T>CMANE SELECT
NM_001300749.3:c.884T>C
NM_001384164.1:c.884T>C
NM_001406751.1:c.875T>C
NM_001406752.1:c.620T>C
NM_139003.3:c.566T>C
NM_139004.3:c.608T>C
NM_139006.3:c.842T>C
NM_139007.3:c.620T>C
NM_139008.3:c.578T>C
NM_139009.3:c.815T>C
NM_139010.3:c.344T>C
NM_139011.3:c.77-167T>C
NP_000401.1:p.Val295Ala
NP_000401.1:p.Val295Ala
NP_001287678.1:p.Val295Ala
NP_001287678.1:p.Val295Ala
NP_001371093.1:p.Val295Ala
NP_001393680.1:p.Val292Ala
NP_001393681.1:p.Val207Ala
NP_620572.1:p.Val189Ala
NP_620573.1:p.Val203Ala
NP_620575.1:p.Val281Ala
NP_620576.1:p.Val207Ala
NP_620577.1:p.Val193Ala
NP_620578.1:p.Val272Ala
NP_620579.1:p.Val115Ala
LRG_748t1:c.884T>C
LRG_748:g.10672T>C
LRG_748p1:p.Val295Ala
NC_000006.11:g.26093180T>C
NM_000410.3:c.884T>C
NM_001300749.2:c.884T>C

Protein change:

V115A

Links:

dbSNP: rs143175221

NCBI 1000 Genomes Browser:

rs143175221

Molecular consequence:

NM_139011.3:c.77-167T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000410.4:c.884T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001300749.3:c.884T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001384164.1:c.884T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406751.1:c.875T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406752.1:c.620T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139003.3:c.566T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139004.3:c.608T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139006.3:c.842T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139007.3:c.620T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139008.3:c.578T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139009.3:c.815T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_139010.3:c.344T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hemochromatosis type 1 (HFE1)
Synonyms:: HFE-Associated Hereditary Hemochromatosis
Identifiers:: MONDO: MONDO:0021001; MedGen: C3469186; OMIM: 235200

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WIPF2 WAS/WASL interacting protein family member 2 [Homo sapiens]
WIPF2 WAS/WASL interacting protein family member 2 [Homo sapiens]
Gene ID:147179

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001313505	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15046077, 17079357, 19787796, 26456104, 12542741, 22624560, 24872867 Citation Link,
SCV005329564	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001313505

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV005329564

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 20, 2023)

germline

clinical testing

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

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

Citations

PubMed

Gene symbol: HFE. Disease: Haemochromatosis.

Bento MC, Ribeiro ML, Relvas L.

Hum Genet. 2004 Mar;114(4):405. No abstract available.

PubMed [citation]

PMID:: 15046077

Heteroduplex analysis for the three common HFE variants: methodology, reliability and analysis of over 5000 requests for testing.

Kingston J, Bowen D, Sweeney M, Lawless S, Jackson H, Worwood M.

J Clin Pathol. 2007 Nov;60(11):1244-8. Epub 2006 Nov 1.

PubMed [citation]

PMID:: 17079357
PMCID:: PMC2095483

See all PubMed Citations (8)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001313505.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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

From Neuberg Centre For Genomic Medicine, NCGM, SCV005329564.1

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

Description

The missense variant c.884T>C(p.Val295Ala) in HFE gene has been reported in heterozygous state in individuals with Hemochromatosis (Barton JC et. al., 2015; Malekzadeh MM et. al., 2014; Jones DC et. al., 2002). Functional studies reporting the observed variant along with another variant (c.829G>A) of HFE gene reveals that both mutations may play a role in the development of Hereditary haemochromatosis (Silva B et. al., 2012). The observed variant has allele frequency of 0.08% in gnomAD exomes database. This variant has been reported to the ClinVar database as Likely benign / Uncertain Significance. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism) predict no damaging effect on protein structure and function for this variant. The amino acid Val at position 295 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to confirm the pathogencity of the variant. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). In the absence of another reportable variant in HFE gene, the molecular diagnosis is not confirmed.

#	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

Last Updated: Oct 20, 2024

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