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NM_014585.6(SLC40A1):c.646A>G (p.Met216Val) AND Hemochromatosis type 4

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Feb 20, 2022
Review status:
criteria provided, conflicting classifications
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:
RCV001137400.7

Allele description [Variation Report for NM_014585.6(SLC40A1):c.646A>G (p.Met216Val)]

NM_014585.6(SLC40A1):c.646A>G (p.Met216Val)

Gene:
SLC40A1:solute carrier family 40 member 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q32.2
Genomic location:
Preferred name:
NM_014585.6(SLC40A1):c.646A>G (p.Met216Val)
HGVS:
  • NC_000002.12:g.189565468T>C
  • NG_009027.1:g.20344A>G
  • NM_014585.6:c.646A>GMANE SELECT
  • NP_055400.1:p.Met216Val
  • LRG_837t1:c.646A>G
  • LRG_837:g.20344A>G
  • NC_000002.11:g.190430194T>C
  • NC_000002.11:g.190430194T>C
  • NM_014585.5:c.646A>G
Protein change:
M216V
Links:
dbSNP: rs757531583
NCBI 1000 Genomes Browser:
rs757531583
Molecular consequence:
  • NM_014585.6:c.646A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hemochromatosis type 4 (HFE4)
Synonyms:
Hemochromatosis, autosomal dominant; Hemochromatosis due to defect in ferroportin
Identifiers:
MONDO: MONDO:0011631; MedGen: C1853733; Orphanet: 139491; OMIM: 606069

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001297334Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Benign
(Apr 27, 2017)
germlineclinical testing

Citation Link,

SCV003276678Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Feb 20, 2022)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001297334.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003276678.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 216 of the SLC40A1 protein (p.Met216Val). This variant is present in population databases (rs757531583, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SLC40A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 895346). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024