NM_000302.4(PLOD1):c.677T>C (p.Val226Ala) AND Ehlers-Danlos syndrome, kyphoscoliotic type 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 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:: RCV001002279.14

Allele description [Variation Report for NM_000302.4(PLOD1):c.677T>C (p.Val226Ala)]

NM_000302.4(PLOD1):c.677T>C (p.Val226Ala)

Gene:

PLOD1:procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.22

Genomic location:

Preferred name:

NM_000302.4(PLOD1):c.677T>C (p.Val226Ala)

HGVS:

NC_000001.11:g.11956950T>C
NG_008159.1:g.27262T>C
NM_000302.4:c.677T>CMANE SELECT
NM_001316320.2:c.818T>C
NP_000293.2:p.Val226Ala
NP_001303249.1:p.Val273Ala
NC_000001.10:g.12017007T>C
NM_000302.3:c.677T>C

Protein change:

V226A

Links:

dbSNP: rs376643174

NCBI 1000 Genomes Browser:

rs376643174

Molecular consequence:

NM_000302.4:c.677T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001316320.2:c.818T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Ehlers-Danlos syndrome, kyphoscoliotic type 1 (EDSKSCL1)
Synonyms:: EHLERS-DANLOS SYNDROME, TYPE VIA; EHLERS-DANLOS SYNDROME, OCULAR-SCOLIOTIC TYPE; Ehlers-Danlos syndrome, hydroxylysine-deficient
Identifiers:: MONDO: MONDO:0016002; MedGen: C0268342; Orphanet: 1900; OMIM: 225400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001160160	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Dec 15, 2018)	germline	clinical testing	Citation Link,
SCV001210239	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 9, 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

SCV001160160

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Dec 15, 2018)

germline

clinical testing

Citation Link,

SCV001210239

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 9, 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

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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001160160.1

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

Description

The PLOD1 c.677T>C; p.Val226Ala variant (rs376643174), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found on two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 226 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Val226Ala 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001210239.4

#	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 valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 226 of the PLOD1 protein (p.Val226Ala). This variant is present in population databases (rs376643174, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PLOD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 811853). 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. 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 16, 2025

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