VCV000094461.24 - ClinVar

NM_004006.3(DMD):c.1337A>G (p.His446Arg)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(1); Likely benign(2)

4 out of 8 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004006.3(DMD):c.1337A>G (p.His446Arg)

Variation ID: 94461 Accession: VCV000094461.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp21.1 X: 32614448 (GRCh38) [ NCBI UCSC ] X: 32632565 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 6, 2015	Feb 25, 2025	Oct 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004006.3:c.1337A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003997.2:p.His446Arg	missense
NM_000109.4:c.1313A>G	NP_000100.3:p.His438Arg	missense
NM_004009.3:c.1325A>G	NP_004000.1:p.His442Arg	missense
NM_004010.3:c.968A>G	NP_004001.1:p.His323Arg	missense
NC_000023.11:g.32614448T>C
NC_000023.10:g.32632565T>C
NG_012232.1:g.730162A>G
LRG_199:g.730162A>G
LRG_199t1:c.1337A>G	LRG_199p1:p.His446Arg
	NP_003997.1:p.His446Arg

... more HGVS ... less HGVS

Protein change

H438R, H323R, H442R

Other names

p.H446R:CAT>CGT

Canonical SPDI

NC_000023.11:32614447:T:C

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00009

The Genome Aggregation Database (gnomAD) 0.00019

The Genome Aggregation Database (gnomAD), exomes 0.00022

The Genome Aggregation Database (gnomAD) 0.00023

The Genome Aggregation Database (gnomAD), exomes 0.00030

Exome Aggregation Consortium (ExAC) 0.00031

Links

ClinGen: CA285523 dbSNP: rs72468699 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DMD		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	11054	11360

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Primary dilated cardiomyopathy	Uncertain significance (1)	no assertion criteria provided	Sep 29, 2014	RCV000157166.9
Left ventricular noncompaction cardiomyopathy	Uncertain significance (1)	no assertion criteria provided	Sep 29, 2014	RCV000157165.9
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Dec 18, 2018	RCV000243647.11
Duchenne muscular dystrophy	Benign (1)	criteria provided, single submitter	Oct 28, 2024	RCV000869409.18
Dilated cardiomyopathy 3B	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001168118.12
not provided	Likely benign (1)	criteria provided, single submitter	May 23, 2018	RCV001719836.10
Becker muscular dystrophy Cardiomyopathy Duchenne muscular dystrophy Dystrophin deficiency	Likely benign (1)	no assertion criteria provided	Jun 26, 2018	RCV001835674.9
DMD-related disorder	Likely benign (1)	no assertion criteria provided	Aug 30, 2022	RCV004542772.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (May 23, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV000235826.8 First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023	Comment: show This variant is associated with the following publications: (PMID: 19937601, 28416588) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (Dec 18, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV000320017.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 19937601 Comment: show This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Apr 27, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Dilated cardiomyopathy 3B	Illumina Laboratory Services, Illumina Accession: SCV001330688.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: show 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Oct 28, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Duchenne muscular dystrophy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001010832.7 First in ClinVar: Dec 17, 2019 Last updated: Feb 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Jun 26, 2018) N Not contributing to aggregate classification	no assertion criteria provided	Becker muscular dystrophy Cardiomyopathy Duchenne muscular dystrophy Dystrophin deficiency	Natera, Inc. Accession: SCV002090378.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Aug 30, 2022) N Not contributing to aggregate classification	no assertion criteria provided	DMD-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004760161.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Sep 29, 2014) N Not contributing to aggregate classification	no assertion criteria provided	Left ventricular noncompaction cardiomyopathy	Blueprint Genetics Accession: SCV000206889.1 First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Uncertain significance (Sep 29, 2014) N Not contributing to aggregate classification	no assertion criteria provided	Primary dilated cardiomyopathy	Blueprint Genetics Accession: SCV000206890.1 First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort.	Flanigan KM	Human mutation	2009	PMID: 19937601

Text-mined citations for rs72468699 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 28, 2025

ClinVar Genomic variation as it relates to human health

NM_004006.3(DMD):c.1337A>G (p.His446Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs72468699 ...