NM_013275.6(ANKRD11):c.7111G>T (p.Ala2371Ser) AND KBG syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 19, 2023
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:: RCV001069182.11

Allele description [Variation Report for NM_013275.6(ANKRD11):c.7111G>T (p.Ala2371Ser)]

NM_013275.6(ANKRD11):c.7111G>T (p.Ala2371Ser)

Gene:

ANKRD11:ankyrin repeat domain containing 11 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q24.3

Genomic location:

Preferred name:

NM_013275.6(ANKRD11):c.7111G>T (p.Ala2371Ser)

HGVS:

NC_000016.10:g.89279431C>A
NG_032003.2:g.216131G>T
NM_001256182.2:c.7111G>T
NM_001256183.2:c.7111G>T
NM_013275.6:c.7111G>TMANE SELECT
NP_001243111.1:p.Ala2371Ser
NP_001243112.1:p.Ala2371Ser
NP_037407.4:p.Ala2371Ser
NC_000016.9:g.89345839C>A
NG_032003.1:g.216131G>T
NM_013275.4:c.7111G>T
NM_013275.5:c.7111G>T

Protein change:

A2371S

Links:

dbSNP: rs747911603

NCBI 1000 Genomes Browser:

rs747911603

Molecular consequence:

NM_001256182.2:c.7111G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001256183.2:c.7111G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_013275.6:c.7111G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: KBG syndrome (KBGS)
Synonyms:: Short stature, characteristic facies, macrodontia, mental retardation, and skeletal anomalies
Identifiers:: MONDO: MONDO:0007846; MedGen: C0220687; Orphanet: 2332; OMIM: 148050

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001234334	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 11, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003818618	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 2, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005045040	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 19, 2023)	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

SCV001234334

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 11, 2019)

germline

clinical testing

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

SCV003818618

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 2, 2020)

germline

clinical testing

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

SCV005045040

Clinical Genomics Laboratory, Washington University in St. Louis

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 19, 2023)

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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001234334.5

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

Description

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ANKRD11-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces alanine with serine at codon 2371 of the ANKRD11 protein (p.Ala2371Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine.

#	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 Revvity Omics, Revvity, SCV003818618.2

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

#	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 Clinical Genomics Laboratory, Washington University in St. Louis, SCV005045040.1

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

Description

The ANKRD11 c.7111G>T (p.Ala2371Ser) variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a germline variant of uncertain significance by three submitters. This variant is only observed on 1/124,112 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors suggest that the variant does not impact ANKRD11 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

#	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: Sep 29, 2024

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