NM_001376.5(DYNC1H1):c.9919G>T (p.Val3307Leu) AND Charcot-Marie-Tooth disease axonal type 2O

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 12, 2020
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:: RCV001250995.6

Allele description [Variation Report for NM_001376.5(DYNC1H1):c.9919G>T (p.Val3307Leu)]

NM_001376.5(DYNC1H1):c.9919G>T (p.Val3307Leu)

Gene:

DYNC1H1:dynein cytoplasmic 1 heavy chain 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.31

Genomic location:

Preferred name:

NM_001376.5(DYNC1H1):c.9919G>T (p.Val3307Leu)

HGVS:

NC_000014.9:g.102032307G>T
NG_008777.1:g.72780G>T
NM_001376.5:c.9919G>TMANE SELECT
NP_001367.2:p.Val3307Leu
NC_000014.8:g.102498644G>T
NC_000014.8:g.102498644G>T
NM_001376.4:c.9919G>T

Protein change:

V3307L

Links:

dbSNP: rs2048518278

NCBI 1000 Genomes Browser:

rs2048518278

Molecular consequence:

NM_001376.5:c.9919G>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Uncertain function

Observations:

Condition(s)

Name:: Charcot-Marie-Tooth disease axonal type 2O
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, AXONAL, TYPE 2O; CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2O; Charcot-Marie-Tooth disease, axonal, type 20; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0013644; MedGen: C3280220; Orphanet: 284232; OMIM: 614228

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001424525	Istituto Neurologico Mediterraneo, Istituto di Ricovero e Cura a Carattere Scientifico	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 26, 2020)	de novo	clinical testing
SCV002189079	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 12, 2020)	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

SCV001424525

Istituto Neurologico Mediterraneo, Istituto di Ricovero e Cura a Carattere Scientifico

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 26, 2020)

de novo

clinical testing

SCV002189079

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 12, 2020)

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
Caucasian	de novo	yes	1	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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Istituto Neurologico Mediterraneo, Istituto di Ricovero e Cura a Carattere Scientifico, SCV001424525.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Invitae, SCV002189079.3

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

Description

This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 3307 of the DYNC1H1 protein (p.Val3307Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant has not been reported in the literature in individuals with DYNC1H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 974689). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DYNC1H1 protein function.

#	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: Mar 5, 2024

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