NM_005334.3(HCFC1):c.3611G>A (p.Arg1204His) AND Methylmalonic acidemia with homocystinuria, type cblX

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 16, 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:: RCV002039949.5

Allele description [Variation Report for NM_005334.3(HCFC1):c.3611G>A (p.Arg1204His)]

NM_005334.3(HCFC1):c.3611G>A (p.Arg1204His)

Gene:

HCFC1:host cell factor C1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq28

Genomic location:

Preferred name:

NM_005334.3(HCFC1):c.3611G>A (p.Arg1204His)

HGVS:

NC_000023.11:g.153954788C>T
NG_012513.1:g.21581G>A
NM_005334.3:c.3611G>AMANE SELECT
NP_005325.2:p.Arg1204His
NC_000023.10:g.153220239C>T

Protein change:

R1204H

Links:

dbSNP: rs782325660

NCBI 1000 Genomes Browser:

rs782325660

Molecular consequence:

NM_005334.3:c.3611G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Methylmalonic acidemia with homocystinuria, type cblX (MAHCX)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 3
Identifiers:: MONDO: MONDO:0010657; MedGen: C0796208; Orphanet: 369962; OMIM: 309541

Recent activity

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JGI_XZT21619.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7598215 5'...
JGI_XZT21619.fwd NIH_XGC_tropTad5 Xenopus tropicalis cDNA clone IMAGE:7598215 5', mRNA sequence
gi|74078160|gnl|dbEST|31243534|gb|C 68.2|

Nucleotide
RecName: Full=Type II phosphatidylinositol 4,5-bisphosphate 4-phosphatase; Short...
RecName: Full=Type II phosphatidylinositol 4,5-bisphosphate 4-phosphatase; Short=Type 2 PtdIns-4,5-P2 4-Ptase; AltName: Full=PtdIns-4,5-P2 4-Ptase II; AltName: Full=Transmembrane protein 55A
gi|82178897|sp|Q5EAU3.1|PP4P2_XENLA

Protein
protein-glutamine gamma-glutamyltransferase K [Homo sapiens]
protein-glutamine gamma-glutamyltransferase K [Homo sapiens]
gi|4507475|ref|NP_000350.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002115053	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 16, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004235269	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 16, 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

SCV002115053

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 16, 2022)

germline

clinical testing

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

SCV004235269

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 16, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002115053.2

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1204 of the HCFC1 protein (p.Arg1204His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with HCFC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1352783). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

#	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 Revvity Omics, Revvity, SCV004235269.1

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

#	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: Sep 29, 2024

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