Table 2.

Selected rare nonsynonymous variants in genes associated with disease.

Chr	Position	SNP ID	Ref Base	Pt DNA	Gene Symbol	Amino Acid Substitution	Gene Name	Associated Disease	Mutation Databases	Functional Prediction	Mode of disease-gene inheritance	Reference
Previously described rare variants in genes associated with common disease
6	160881127	rs3798220	T	CT	LPA	I4399M*	Apolipoprotein(a) Precursor (Lp(a))	Coronary artery disease	Associated with high Lp(a)	Benign	n/a	20, 21
2	183411581	rs288326	G	AG	FRZB	R200W	Frizzled-related protein	Osteoarthritis	Possibly associated with osteoarthritis**	Damaging	n/a	34
Previously described rare variants in genes associated with rare disease
6	26199158	rs1799945	C	CG	HFE	H63D	Hereditary haemochromatosi s protein Precursor	Haemochromatosis	Probably disease associated	Damaging	recessive, incomplete penetrance	35, 36
3	15661697	rs13078881	G	CG	BTD	D444H	Biotinidase Precursor	Biotinidase Deficiency	previously described, intermediate phenotype	Damaging	recessive	37
5	149340823	none	C	CT	SLC26A2	R492W	Solute carrier family 26 (sulfate transporter), Member 2	Diastrophic dysplasia	disease associated	Damaging	recessive	38
1	207865689	none	G	AG	LAMB3	R635X	Laminin Beta-3	Epidermolysis Bullosa, Junctional	disease associated, most common mutation	Truncated protein	recessive	39
2	44393296	none	T	CT	SLC3A1	M467T	Solute carrier family 3 (cystine, dibasic, and neutral amino acid transporter) Member 1	Cystinuria	disease associated, most common mutation	Damaging	recessive	40
Previously described variants of unknown significance in disease associated genes
3	14146021	none	A	AG	TMEM43	M41V	Transmembrane protein 43	Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy	found in 1 of 150 probands with ARVC	Benign	dominant, incomplete penetrance	13
11	47324447	rs34580776	C	CT	MYBPC3	R326Q	Myosin-binding protein C, cardiac-type	Familial Hypertrophic Cardiomyopathy	variant of unknown significance	Intermediate	dominant, incomplete penetrance	41
13	31870584	none	A	AG	BRCA2	I3312V	Breast cancer type 2 susceptibility protein	Breast Cancer	variant of unknown significance	Intermediate	dominant, loss of heterozygo sity	42
Novel variants potentially associated with rare disease
6	7528007	novel	G	AG	DSP	R1838H	Desmoplakin	Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy	not found	Damaging	dominant, incomplete penetrance	13
1	191468879	novel	C	CT	HRPT2	Q430X	Parafibromin	Hyperparathyroidism -Jaw Tumour	not found	Truncated protein	dominant, loss of heterozygo sity	43
7	93888305	novel	C	CT	COL1A2	P782S	Alpha-2 type I collagen	Ehlers-Danlos Syndrome, Type VII	not found	Intermediate	recessive	44
7	116976093	novel	G	AG	CFTR	G458R	Cystic fibrosis transmembrane conductance regulator	Cystic Fibrosis	not found	Damaging	recessive	45
19	40467780	novel	A	AG	HAMP	T84A	Hepcidin Precursor	Haemochromatosis, Juvenile	not found	Intermediate	recessive
1	144127058	novel	C	CT	HFE2	H174Y	Hemojuvelin Precursor	Haemochromatosis, Juvenile	not found	Damaging	recessive

Rare nonsynonymous variants in genes associated with inherited disease. 1 - RefSeq reference allele in the human genome reference sequence (RefSeq), build 36. 2 - Disease associated with inherited mutations in the gene evaluated. 3 - Mutation databases evaluated for presence of the found variant in multiple mutation databases, including UniProt protein variant database, Human Genome Mutation Database curated mutation database, Locus-Specific Mutation Databases (curated by the Human Genome Variation Society), Online Mendelian Inheritance in Man, and clinical testing laboratory databases together with associated links. 4 - Functional prediction; Prediction of functional effect of mutation, derived from substitution effect prediction algorithms, Polymorphism Phenotyping (PolyPhen) and Sorting Intolerant from Tolerant (SIFT); published in vitro experimental evidence,; and evaluation of typical mutational mechanism in other disease gene associated mutations.

^*Also reported as I1891M. Each copy of C allele increases lipoprotein(a) level 1.8 SD and risk for coronary artery disease 2–3 fold.

^**Inconclusive association in metaanalysis of osteoarthritis related SNPs though moderate association with severe hip osteoarthritis.