NM_019032.6(ADAMTSL4):c.2977C>T (p.Arg993Trp) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 9, 2022
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:: RCV002308917.3

Allele description

NM_019032.6(ADAMTSL4):c.2977C>T (p.Arg993Trp)

Gene:

ADAMTSL4:ADAMTS like 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q21.2

Genomic location:

Preferred name:

NM_019032.6(ADAMTSL4):c.2977C>T (p.Arg993Trp)

HGVS:

NC_000001.11:g.150559794C>T
NG_012172.1:g.15373C>T
NM_001288607.2:c.2860C>T
NM_001288608.2:c.3046C>T
NM_001378596.1:c.2977C>T
NM_019032.4:c.2977C>T
NM_019032.6:c.2977C>TMANE SELECT
NP_001275536.1:p.Arg954Trp
NP_001275537.1:p.Arg1016Trp
NP_001365525.1:p.Arg993Trp
NP_061905.2:p.Arg993Trp
NC_000001.10:g.150532270C>T
NM_019032.5:c.2977C>T
NM_019032.6:c.2977C>T

Protein change:

R1016W

Molecular consequence:

NM_001288607.2:c.2860C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001288608.2:c.3046C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378596.1:c.2977C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_019032.6:c.2977C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Homo sapiens gephyrin (GPHN), transcript variant 2, mRNA
Homo sapiens gephyrin (GPHN), transcript variant 2, mRNA
gi|1799657594|ref|NM_001024218.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002601181	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 9, 2022)	germline	clinical testing	Citation Link,
SCV003480288	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 28, 2022)	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

SCV002601181

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 9, 2022)

germline

clinical testing

Citation Link,

SCV003480288

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 28, 2022)

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
not provided	germline	yes	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

Details of each submission

From GeneDx, SCV002601181.2

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Sanchez_2012_Abstract)

#	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

From Invitae, SCV003480288.1

#	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 tryptophan, which is neutral and slightly polar, at codon 993 of the ADAMTSL4 protein (p.Arg993Trp). This variant is present in population databases (rs202246511, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ADAMTSL4-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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

Last Updated: May 1, 2024

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