NM_000426.4(LAMA2):c.1814C>T (p.Thr605Ile) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 20, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001288666.6

Allele description [Variation Report for NM_000426.4(LAMA2):c.1814C>T (p.Thr605Ile)]

NM_000426.4(LAMA2):c.1814C>T (p.Thr605Ile)

Gene:

LAMA2:laminin subunit alpha 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q22.33

Genomic location:

Preferred name:

NM_000426.4(LAMA2):c.1814C>T (p.Thr605Ile)

HGVS:

NC_000006.12:g.129250143C>T
NG_008678.1:g.372003C>T
NM_000426.4:c.1814C>TMANE SELECT
NM_001079823.2:c.1814C>T
NP_000417.2:p.Thr605Ile
NP_000417.3:p.Thr605Ile
NP_001073291.2:p.Thr605Ile
LRG_409t1:c.1814C>T
LRG_409:g.372003C>T
LRG_409p1:p.Thr605Ile
NC_000006.11:g.129571288C>T
NM_000426.3:c.1814C>T

Protein change:

T605I

Links:

dbSNP: rs112388307

NCBI 1000 Genomes Browser:

rs112388307

Molecular consequence:

NM_000426.4:c.1814C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079823.2:c.1814C>T - 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
SCV001475944	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Nov 6, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001550932	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
SCV003816312	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 20, 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

SCV001475944

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Uncertain significance
(Nov 6, 2019)

unknown

clinical testing

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

SCV001550932

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

SCV003816312

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jul 20, 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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

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 Athena Diagnostics, SCV001475944.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001550932.1

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

Description

The LAMA2 p.Thr605Ile variant was not identified in the literature nor was it identified in GeneInsight-COGR, Cosmic, and LOVD 3.0. The variant was identified in dbSNP (ID: rs112388307) and ClinVar (classified as likely benign by GeneDx). The variant was also identified in control databases in 99 of 282574 chromosomes at a frequency of 0.00035 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 90 of 24970 chromosomes (freq: 0.003604), Latino in 5 of 35432 chromosomes (freq: 0.000141), Other in 1 of 7216 chromosomes (freq: 0.000139), European (Finnish) in 1 of 25030 chromosomes (freq: 0.00004), European (non-Finnish) in 2 of 129026 chromosomes (freq: 0.000016), while the variant was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Thr605 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 Revvity Omics, Revvity, SCV003816312.2

#	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

Last Updated: Oct 26, 2024

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