NM_001197104.2(KMT2A):c.11246G>A (p.Arg3749His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 19, 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:: RCV002041137.8

Allele description [Variation Report for NM_001197104.2(KMT2A):c.11246G>A (p.Arg3749His)]

NM_001197104.2(KMT2A):c.11246G>A (p.Arg3749His)

Genes:

TTC36-AS1:TTC36 and KMT2A antisense RNA 1 [Gene - HGNC]
KMT2A:lysine methyltransferase 2A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_001197104.2(KMT2A):c.11246G>A (p.Arg3749His)

HGVS:

NC_000011.10:g.118519717G>A
NG_027813.1:g.88228G>A
NM_001197104.2:c.11246G>AMANE SELECT
NM_005933.4:c.11237G>A
NP_001184033.1:p.Arg3749His
NP_005924.2:p.Arg3746His
LRG_613t1:c.11246G>A
LRG_613:g.88228G>A
NC_000011.9:g.118390432G>A
NM_001197104.1:c.11246G>A

Protein change:

R3746H

Links:

dbSNP: rs781945281

NCBI 1000 Genomes Browser:

rs781945281

Molecular consequence:

NM_001197104.2:c.11246G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005933.4:c.11237G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002309587	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 19, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28191889, 31102422, 33004838, 28492532
SCV002562347	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Aug 9, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002309587

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 19, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002562347

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Aug 9, 2022)

germline

clinical testing

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

Citations

PubMed

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.

Stessman HA, Xiong B, Coe BP, Wang T, Hoekzema K, Fenckova M, Kvarnung M, Gerdts J, Trinh S, Cosemans N, Vives L, Lin J, Turner TN, Santen G, Ruivenkamp C, Kriek M, van Haeringen A, Aten E, Friend K, Liebelt J, Barnett C, Haan E, et al.

Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.

PubMed [citation]

PMID:: 28191889
PMCID:: PMC5374041

Predisposing germline mutations in high hyperdiploid acute lymphoblastic leukemia in children.

de Smith AJ, Lavoie G, Walsh KM, Aujla S, Evans E, Hansen HM, Smirnov I, Kang AY, Zenker M, Ceremsak JJ, Stieglitz E, Muskens IS, Roberts W, McKean-Cowdin R, Metayer C, Roux PP, Wiemels JL.

Genes Chromosomes Cancer. 2019 Oct;58(10):723-730. doi: 10.1002/gcc.22765. Epub 2019 May 27.

PubMed [citation]

PMID:: 31102422
PMCID:: PMC6684857

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002309587.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3749 of the KMT2A protein (p.Arg3749His). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1517628). This missense change has been observed in individual(s) with acute lymphoblastic leukemia, intellectual disability and/or neurodevelopmental disorders (PMID: 28191889, 31102422, 33004838). This variant is present in population databases (rs781945281, gnomAD 0.02%).

#	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 GeneDx, SCV002562347.2

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

Description

See Variant Classification Assertion Criteria.

#	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: Feb 20, 2024

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