NM_004006.3(DMD):c.1095A>C (p.Gln365His) AND not specified

Clinical significance:Benign (Last evaluated: Jun 25, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000367474.6

Allele description [Variation Report for NM_004006.3(DMD):c.1095A>C (p.Gln365His)]

NM_004006.3(DMD):c.1095A>C (p.Gln365His)

Gene:
DMD:dystrophin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xp21.1
Genomic location:
Preferred name:
NM_004006.3(DMD):c.1095A>C (p.Gln365His)
HGVS:
  • NC_000023.11:g.32645018T>G
  • NG_012232.1:g.699592A>C
  • NM_000109.4:c.1071A>C
  • NM_004006.2:c.1095A>C
  • NM_004006.3:c.1095A>CMANE SELECT
  • NM_004009.3:c.1083A>C
  • NM_004010.3:c.726A>C
  • NP_000100.3:p.Gln357His
  • NP_003997.1:p.Gln365His
  • NP_003997.2:p.Gln365His
  • NP_004000.1:p.Gln361His
  • NP_004001.1:p.Gln242His
  • LRG_199t1:c.1095A>C
  • LRG_199:g.699592A>C
  • LRG_199p1:p.Gln365His
  • NC_000023.10:g.32663135T>G
  • p.Gln365His
Protein change:
Q242H
Links:
dbSNP: rs1800266
NCBI 1000 Genomes Browser:
rs1800266
Molecular consequence:
  • NM_000109.4:c.1071A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004006.2:c.1095A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004006.3:c.1095A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004009.3:c.1083A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004010.3:c.726A>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000333986EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Benign
(Sep 7, 2015)
germlineclinical testing

Citation Link,

SCV000966290Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Benign
(Jan 18, 2019)
germlineclinical testing

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

SCV001372390Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Benign
(Jun 25, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort.

Flanigan KM, Dunn DM, von Niederhausern A, Soltanzadeh P, Gappmaier E, Howard MT, Sampson JB, Mendell JR, Wall C, King WM, Pestronk A, Florence JM, Connolly AM, Mathews KD, Stephan CM, Laubenthal KS, Wong BL, Morehart PJ, Meyer A, Finkel RS, Bonnemann CG, Medne L, et al.

Hum Mutat. 2009 Dec;30(12):1657-66. doi: 10.1002/humu.21114.

PubMed [citation]
PMID:
19937601
PMCID:
PMC3404892

Details of each submission

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000333986.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000966290.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The p.Gln365His variant in DMD is classified as benign because it has been ident ified in 0.15% (29/19076) of South Asian chromosomes including 16 hemizygotes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP criteria applied: BA1.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001372390.1

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

Description

Variant summary: DMD c.1095A>C (p.Gln365His) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 183391 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 136 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1095A>C has been reported in the literature as a benign sequence variant in a cohort of patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy (Flanigan_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign, n=5). Based on the evidence outlined above, the variant was classified as benign.

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

Last Updated: Nov 6, 2021

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