NM_002907.4(RECQL):c.1877A>G (p.Lys626Arg) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 19, 2024
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:: RCV001358456.5

Allele description [Variation Report for NM_002907.4(RECQL):c.1877A>G (p.Lys626Arg)]

NM_002907.4(RECQL):c.1877A>G (p.Lys626Arg)

Genes:

RECQL:RecQ like helicase [Gene - OMIM - HGNC]
PYROXD1:pyridine nucleotide-disulphide oxidoreductase domain 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p12.1

Genomic location:

Preferred name:

NM_002907.4(RECQL):c.1877A>G (p.Lys626Arg)

HGVS:

NC_000012.12:g.21470267T>C
NG_053196.1:g.37664T>C
NM_001350912.2:c.*1513T>C
NM_001350913.2:c.*1513T>C
NM_002907.4:c.1877A>GMANE SELECT
NM_024854.5:c.*1513T>CMANE SELECT
NM_032941.3:c.1877A>G
NP_002898.2:p.Lys626Arg
NP_116559.1:p.Lys626Arg
NC_000012.11:g.21623201T>C
NM_002907.3:c.1877A>G

Protein change:

K626R

Links:

dbSNP: rs555780310

NCBI 1000 Genomes Browser:

rs555780310

Molecular consequence:

NM_001350912.2:c.*1513T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001350913.2:c.*1513T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_024854.5:c.*1513T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_002907.4:c.1877A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_032941.3:c.1877A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001554193	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV001566576	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002758802	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 3, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001554193

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Uncertain significance

unknown

clinical testing

SCV001566576

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 19, 2024)

germline

clinical testing

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

SCV002758802

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jun 3, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001554193.1

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

Description

The RECQL p.Lys626Arg variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs555780310) and in control databases in 8 of 240596 chromosomes at a frequency of 0.000033 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5812 chromosomes (freq: 0.000172), Latino in 4 of 32480 chromosomes (freq: 0.000123) and European (non-Finnish) in 3 of 109994 chromosomes (freq: 0.000027), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The p.Lys626 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

From Invitae, SCV001566576.4

#	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 lysine, which is basic and polar, with arginine, which is basic and polar, at codon 626 of the RECQL protein (p.Lys626Arg). This variant is present in population databases (rs555780310, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RECQL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1050702). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

From GeneDx, SCV002758802.1

#	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 does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

#	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

Last Updated: Jun 9, 2024

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